ClinVar Genomic variation as it relates to human health
NM_004004.6(GJB2):c.585G>C (p.Met195Ile)
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.
Likely pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004004.6(GJB2):c.585G>C (p.Met195Ile)
Variation ID: 1334161 Accession: VCV001334161.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 13q12.11 13: 20188997 (GRCh38) [ NCBI UCSC ] 13: 20763136 (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 Jan 15, 2022 May 12, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004004.6:c.585G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003995.2:p.Met195Ile missense NC_000013.11:g.20188997C>G NC_000013.10:g.20763136C>G NG_008358.1:g.8979G>C LRG_1350:g.8979G>C LRG_1350t1:c.585G>C LRG_1350p1:p.Met195Ile - Protein change
- M195I
- Other names
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- Canonical SPDI
- NC_000013.11:20188996:C:G
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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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0.00060 (G)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00047
1000 Genomes Project 0.00060
- Links
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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GJB2 | Dosage sensitivity unlikely | No evidence available |
GRCh38 GRCh37 |
557 | 620 |
Conditions - Germline
Condition
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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
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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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Oct 1, 2021 | RCV001810542.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV001869610.3 |
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
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
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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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Uncertain significance
(Oct 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV002060084.2
First in ClinVar: Jan 15, 2022 Last updated: Dec 24, 2022 |
Comment:
NM_004004.5(GJB2):c.585G>C(M195I) is a missense variant classified as a variant of uncertain significance in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. M195I has … (more)
NM_004004.5(GJB2):c.585G>C(M195I) is a missense variant classified as a variant of uncertain significance in the context of GJB2-related DFNB1 nonsyndromic hearing loss and deafness. M195I has been observed in cases with relevant disease (PMID: 18941476, 22925408, 20601923). Functional assessments of this variant are not available in the literature. M195I has been observed in population frequency databases (gnomAD: SAS 0.07%). In summary, there is insufficient evidence to classify NM_004004.5(GJB2):c.585G>C(M195I) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less)
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Likely pathogenic
(Jan 18, 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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Invitae
Accession: SCV002312322.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 195 of the GJB2 protein (p.Met195Ile). … (more)
This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 195 of the GJB2 protein (p.Met195Ile). This variant is present in population databases (rs570552952, gnomAD 0.07%). This missense change has been observed in individual(s) with clinical features of autosomal recessive nonsyndromic deafness (PMID: 29148562). This variant has been reported in individual(s) with clinical features of autosomal dominant nonsyndromic deafness (PMID: 18941476, 20601923); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 1334161). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB2 protein function with a positive predictive value of 95%. This variant disrupts the p.Met195 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19125024, 19366456, 20497192, 21366436, 24013081, 30146550). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive nonsyndromic hearing loss 1A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV005042746.1
First in ClinVar: May 12, 2024 Last updated: May 12, 2024 |
Comment:
The missense variant c.585G>Cp.Met195Ile in GJB2 gene has been reported previously in homozygous and heterozygous state in individuals with hearing loss de la Luz Arenas-Sordo … (more)
The missense variant c.585G>Cp.Met195Ile in GJB2 gene has been reported previously in homozygous and heterozygous state in individuals with hearing loss de la Luz Arenas-Sordo M, 2012, Mani RS, et al., 2009. The variant is reported with 0.001% allele frequency in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic/ Uncertain Significance. However, experimental studies on the pathogenicity of the variant are not available. The amino acid Methionine at position 195 is changed to a Isoleucine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by SIF. The amino acid change p.Met195Ile in GJB2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (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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Children with GJB2 gene mutations have various audiological phenotypes. | Wang X | Bioscience trends | 2018 | PMID: 30146550 |
Recurrence of reported CDH23 mutations causing DFNB12 in a special cohort of South Indian hearing impaired assortative mating families - an evaluation. | Vanniya S P | Annals of human genetics | 2018 | PMID: 29148562 |
GJB2-associated hearing loss undetected by hearing screening of newborns. | Minami SB | Gene | 2013 | PMID: 24013081 |
Unique spectrum of GJB2 mutations in Mexico. | de la Luz Arenas-Sordo M | International journal of pediatric otorhinolaryngology | 2012 | PMID: 22925408 |
GJB2 allele variants and the associated audiologic features identified in Chinese patients with less severe idiopathic hearing loss. | Zhang J | Genetic testing and molecular biomarkers | 2011 | PMID: 21366436 |
Prevalence of Connexin 26 (GJB2) and Pendred (SLC26A4) mutations in a population of adult cochlear implant candidates. | Hochman JB | Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology | 2010 | PMID: 20601923 |
A large cohort study of GJB2 mutations in Japanese hearing loss patients. | Tsukada K | Clinical genetics | 2010 | PMID: 20497192 |
GJB2 mutation spectrum in 2,063 Chinese patients with nonsyndromic hearing impairment. | Dai P | Journal of translational medicine | 2009 | PMID: 19366456 |
Prevalence of GJB2 (connexin-26) and GJB6 (connexin-30) mutations in a cohort of 300 Brazilian hearing-impaired individuals: implications for diagnosis and genetic counseling. | Batissoco AC | Ear and hearing | 2009 | PMID: 19125024 |
Functional consequences of novel connexin 26 mutations associated with hereditary hearing loss. | Mani RS | European journal of human genetics : EJHG | 2009 | PMID: 18941476 |
Text-mined citations for rs570552952 ...
HelpRecord last updated May 19, 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.