ClinVar Genomic variation as it relates to human health
NM_003560.4(PLA2G6):c.1186+1G>A
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_003560.4(PLA2G6):c.1186+1G>A
Variation ID: 635025 Accession: VCV000635025.28
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.1 22: 38129453 (GRCh38) [ NCBI UCSC ] 22: 38525460 (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 Jun 24, 2019 May 12, 2024 Jan 4, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003560.4:c.1186+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001004426.3:c.1186+1G>A splice donor NM_001199562.3:c.1186+1G>A splice donor NM_001349864.2:c.1186+1G>A splice donor NM_001349865.2:c.1186+1G>A splice donor NM_001349866.2:c.1186+1G>A splice donor NM_001349867.2:c.652+1G>A splice donor NM_001349868.2:c.508+1G>A splice donor NM_001349869.2:c.652+1G>A splice donor NC_000022.11:g.38129453C>T NC_000022.10:g.38525460C>T NG_007094.3:g.90326G>A LRG_1015:g.90326G>A LRG_1015t1:c.1186+1G>A - Protein change
- Other names
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- Canonical SPDI
- NC_000022.11:38129452: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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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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PLA2G6 | - | - |
GRCh38 GRCh37 |
1045 | 1076 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2024 | RCV000785898.6 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 23, 2023 | RCV001310807.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002535731.3 |
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
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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
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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
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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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Likely pathogenic
(Jun 15, 2018)
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criteria provided, single submitter
Method: research
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Infantile neuroaxonal dystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV000924474.1
First in ClinVar: Jun 24, 2019 Last updated: Jun 24, 2019 |
Comment:
The homozygous c.1186+1G>A variant was identified by our study in one individual with neurodegeneration with brain iron accumulation. This variant has been identified in the … (more)
The homozygous c.1186+1G>A variant was identified by our study in one individual with neurodegeneration with brain iron accumulation. This variant has been identified in the literature in one proband who was compound heterozygous for the c.1186+1G>A variant as well as the c.895-1G>A variant (Tonelli et al. 2010, PMID: 20584031). This variant has been identified in <0.01% (1/15304) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs761815070). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The c.1186+1G>A variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the PLA2G6 gene is an established disease mechanism in autosomal recessive Neurodegeneration with Brain Iron Accumulation, and this is a loss of function variant. In summary, although additional studies are required to fully establish its pathogenicity, this variant is likely pathogenic. (less)
Clinical Features:
Abnormality of brain morphology (present)
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Pathogenic
(Oct 23, 2023)
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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: SCV001875287.4
First in ClinVar: Sep 19, 2021 Last updated: Nov 25, 2023 |
Comment:
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed … (more)
Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 20584031, 32404165) (less)
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Pathogenic
(Jan 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Infantile neuroaxonal dystrophy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002232715.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects a donor splice site in intron 8 of the PLA2G6 gene. RNA analysis indicates that disruption of this splice site induces … (more)
This sequence change affects a donor splice site in intron 8 of the PLA2G6 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs761815070, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with clinical features of infantile neuroaxonal dystrophy (PMID: 20584031, 32404165; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 635025). Studies have shown that disruption of this splice site results in alternative splicing and introduces a premature termination codon (PMID: 20584031). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Oct 01, 2020)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500748.18
First in ClinVar: Mar 14, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jan 24, 2023)
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criteria provided, single submitter
Method: curation
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PLA2G6-associated neurodegeneration
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761003.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The homozygous c.1186+1G>A variant in PLA2G6 was identified by our study in 1 individual with PLA2G6-associated neurodegeneration. The c.1186+1G>A variant in PLA2G6 has been reported … (more)
The homozygous c.1186+1G>A variant in PLA2G6 was identified by our study in 1 individual with PLA2G6-associated neurodegeneration. The c.1186+1G>A variant in PLA2G6 has been reported in 1 compound heteroyzgous individual with PLA2G6-associated neurodegeneration (PMID: 20584031) and has been identified in 0.006% (1/16250) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs761815070). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 437465) and has been interpreted as pathogenic or likely pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen, GeneDx, Invitae, and Broad Institute Rare Disease Group (Broad Institute). This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the PLA2G6 gene is an established disease mechanism in autosomal recessive PLA2G6-associated neurodegeneration. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3_supporting (Richards 2015). (less)
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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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Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families. | Issa MY | BMC medical genomics | 2020 | PMID: 32404165 |
Novel splice-site mutations and a large intragenic deletion in PLA2G6 associated with a severe and rapidly progressive form of infantile neuroaxonal dystrophy. | Tonelli A | Clinical genetics | 2010 | PMID: 20584031 |
Text-mined citations for rs761815070 ...
HelpRecord last updated May 27, 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.