ClinVar Genomic variation as it relates to human health
NM_018972.4(GDAP1):c.487C>T (p.Gln163Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_018972.4(GDAP1):c.487C>T (p.Gln163Ter)
Variation ID: 4193 Accession: VCV000004193.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q21.11 8: 74361886 (GRCh38) [ NCBI UCSC ] 8: 75274121 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Feb 14, 2024 Jan 3, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_018972.4:c.487C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_061845.2:p.Gln163Ter nonsense NM_001040875.4:c.283C>T NP_001035808.1:p.Gln95Ter nonsense NM_001362929.2:c.160C>T NP_001349858.1:p.Gln54Ter nonsense NM_001362930.2:c.313C>T NP_001349859.1:p.Gln105Ter nonsense NM_001362931.2:c.487C>T NP_001349860.1:p.Gln163Ter nonsense NM_001362932.2:c.160C>T NP_001349861.1:p.Gln54Ter nonsense NC_000008.11:g.74361886C>T NC_000008.10:g.75274121C>T NG_008787.3:g.45757C>T LRG_244:g.45757C>T LRG_244t1:c.487C>T - Protein change
- Q163*, Q105*, Q54*, Q95*
- Other names
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- Canonical SPDI
- NC_000008.11:74361885:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00008
The Genome Aggregation Database (gnomAD) 0.00015
Trans-Omics for Precision Medicine (TOPMed) 0.00017
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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GDAP1 | - | - |
GRCh38 GRCh37 |
495 | 589 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Apr 1, 2005 | RCV000004413.3 | |
not provided (1) |
no classification provided
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- | RCV000031963.3 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Dec 17, 2023 | RCV000204463.13 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2024 | RCV000236485.12 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763605.2 | |
Conflicting interpretations of pathogenicity (3) |
no assertion criteria provided
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Aug 14, 2019 | RCV000857207.6 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Feb 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Athena Diagnostics
Accession: SCV001880593.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
Comment:
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with … (more)
This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
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Pathogenic
(Jan 03, 2022)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 4A
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002058858.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
Comment:
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are … (more)
Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000076, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004193, PMID:11743580, 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Gait disturbance (present) , Attention deficit hyperactivity disorder (present) , Neuropathic arthropathy (present) , Demyelinating peripheral neuropathy (present) , Gait ataxia (present) , Peripheral axonal … (more)
Gait disturbance (present) , Attention deficit hyperactivity disorder (present) , Neuropathic arthropathy (present) , Demyelinating peripheral neuropathy (present) , Gait ataxia (present) , Peripheral axonal degeneration (present) , Sensory neuropathy (present) (less)
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Pathogenic
(Jan 03, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024235.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 4A
Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive Charcot-Marie-Tooth disease axonal type 2K Charcot-Marie-Tooth disease recessive intermediate A
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894451.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Jun 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000292799.11
First in ClinVar: Jul 24, 2016 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11743580, 31827005, 25525159, 25403865, 12601710, 26257172, 21519004, 26848201, 15805163, 33903021, 33187793, 31589614) (less)
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Pathogenic
(Dec 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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Charcot-Marie-Tooth disease type 4A
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000260870.11
First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln163*) in the GDAP1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln163*) in the GDAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GDAP1 are known to be pathogenic (PMID: 11743580). This variant is present in population databases (rs104894077, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 11743580, 12601710, 20849849). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4193). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 01, 2005)
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no assertion criteria provided
Method: literature only
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NEUROPATHY, AXONAL, WITH VOCAL CORD PARESIS, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024586.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 21, 2016 |
Comment on evidence:
In a large inbred Spanish family with autosomal recessive distal axonal neuropathy with hoarseness and vocal cord paresis (607706), Cuesta et al. (2002) found that … (more)
In a large inbred Spanish family with autosomal recessive distal axonal neuropathy with hoarseness and vocal cord paresis (607706), Cuesta et al. (2002) found that affected members were homoallelic for a gln163-to-stop (Q163X) mutation in the GDAP1 gene, caused by a C-to-T transition at nucleotide 487. In another smaller family, affected members were compound heterozygotes for the Q163X and S194X (606598.0002) mutations in the GDAP1 gene. Boerkoel et al. (2003) identified homozygosity for the Q163X mutation in 5 patients from 3 unrelated Hispanic families with an early onset form of autosomal recessive CMT. Based on the finding of a common pathogenic haplotype among all patients, the authors suggested that the Q163X mutation is a founder mutation that may have arisen in Spain. Clinical features of these patients included onset at about the first year of life, with severe distal muscle weakness leading to disability in the second decade of life. One patient had vocal cord weakness. Nerve conduction velocities in 2 patients were consistent with axonal CMT. Histopathologic changes showed both demyelination and axonal loss, as well as onion bulb formations. Claramunt et al. (2005) identified homozygosity for the Q163X mutation in affected probands from 4 unrelated families with axonal neuropathy and vocal cord paresis. All patients were of Spanish ancestry. Haplotype analysis indicated a founder effect originating in the Iberian peninsula approximately 33,000 years ago. (less)
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Likely pathogenic
(-)
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no assertion criteria provided
Method: provider interpretation
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
inherited
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Inherited Neuropathy Consortium
Accession: SCV001190053.1
First in ClinVar: Mar 26, 2020 Last updated: Mar 26, 2020 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955406.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Uncertain significance
(Jan 06, 2016)
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no assertion criteria provided
Method: literature only
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Charcot-Marie-Tooth disease type 4A
Affected status: yes
Allele origin:
germline
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Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004174591.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Uncertain significance
(Aug 14, 2019)
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no assertion criteria provided
Method: research
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Charcot-Marie-Tooth disease
Affected status: yes
Allele origin:
germline
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Genesis Genome Database
Accession: SCV000999789.1
First in ClinVar: Dec 06, 2019 Last updated: Dec 06, 2019 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001925095.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Charcot-Marie-Tooth disease
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV001750197.2
First in ClinVar: Jul 15, 2021 Last updated: Oct 01, 2022 |
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not provided
(-)
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no classification provided
Method: literature only
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Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive
Affected status: not provided
Allele origin:
unknown
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GeneReviews
Accession: SCV000054655.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical and molecular evidence of possible digenic inheritance for MFN2/GDAP1 genes in Charcot-Marie-Tooth disease. | Barreda Fierro R | Neuromuscular disorders : NMD | 2020 | PMID: 33187793 |
Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. | Adam MP | - | 2016 | PMID: 20301641 |
Charcot Marie Tooth disease (CMT4A) due to GDAP1 mutation: report of a Colombian family. | Martin AM | Colombia medica (Cali, Colombia) | 2015 | PMID: 26848201 |
Simultaneous MFN2 and GDAP1 mutations cause major mitochondrial defects in a patient with CMT. | Cassereau J | Neurology | 2011 | PMID: 21519004 |
Mitochondrial dysfunction and pathophysiology of Charcot-Marie-Tooth disease involving GDAP1 mutations. | Cassereau J | Experimental neurology | 2011 | PMID: 20849849 |
Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. | Claramunt R | Journal of medical genetics | 2005 | PMID: 15805163 |
CMT4A: identification of a Hispanic GDAP1 founder mutation. | Boerkoel CF | Annals of neurology | 2003 | PMID: 12601710 |
The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. | Cuesta A | Nature genetics | 2002 | PMID: 11743580 |
Text-mined citations for rs104894077 ...
HelpRecord last updated May 08, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.