Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

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Variant: NM_004004.6(GJB2):c.585G>C (p.Met195Ile)

CA6904231

1334161 (ClinVar)

Gene: GJB2

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 6a7f9cef-29bc-4466-a84c-d9741f7e1a47

Approved on: 2024-05-15

Published on: 2024-07-02

HGVS expressions

NM_004004.6:c.585G>C

NM_004004.6(GJB2):c.585G>C (p.Met195Ile)

NC_000013.11:g.20188997C>G

CM000675.2:g.20188997C>G

NC_000013.10:g.20763136C>G

CM000675.1:g.20763136C>G

NC_000013.9:g.19661136C>G

NG_008358.1:g.8979G>C

ENST00000382844.2:c.585G>C

ENST00000382848.5:c.585G>C

ENST00000382844.1:c.585G>C

ENST00000382848.4:c.585G>C

NM_004004.5:c.585G>C

Uncertain Significance

PM5 PP3

PM2

Evidence Links 0

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The c.585G>C is a missense variant predicted to cause a substitution of methionine by isoleucine at amino acid 195 (p.Met195Ile). The highest population minor allele frequency in gnomAD v4.1.0 is 0.048% (56/91086, CI 95%) in the East Asian population (PM2_Supporting, BS1, and BA1 are not met). The c.585G>C (p.Met195Ile) variant has been detected in two patients with hearing loss but without a second variant (PMID: 20601923; 18941476). The computational predictor REVEL gives a score of 0.928 which is above the threshold of 0.7, evidence that correlates with impact to GJB2 function (PP3). Another missense variant c.583G>C (p.Met195Val; ClinVar Variation ID: 22537) in the same codon has been classified as pathogenic for hearing loss by the ClinGen Hearing Loss VCEP (PM5). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive non-syndromic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (PP3, PM5; Version 2; 5/15/24).

PM5

c.583A>G p.Met195Val is classified as Pathogenic by the HL-VCEP.

PP3

Revel Score: 0.928

PM2

0,048%. (56/91086 south asian alleles with 95% CI). Neither PM2_supporting nor BS1_Suppporting were met.

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