The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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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
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
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Uncertain Significance

Met criteria codes 2
PP3 PM5
Not Met criteria codes 1
PM2

Evidence Links 0

Expert Panel

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

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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).
Met criteria codes
PP3
Revel Score: 0.928
PM5
c.583A>G p.Met195Val is classified as Pathogenic by the HL-VCEP.
Not Met criteria codes
PM2
0,048%. (56/91086 south asian alleles with 95% CI). Neither PM2_supporting nor BS1_Suppporting were met.
Curation History
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