Variant: NM_004004.6(GJB2):c.583A>G (p.Met195Val)

CA6904233

225375 (ClinVar)

Gene: GJB2

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: 956244b5-ee05-47cd-98e0-a3c8fa5f5bc9

HGVS expressions

NM_004004.6:c.583A>G
NM_004004.6(GJB2):c.583A>G (p.Met195Val)
NC_000013.11:g.20188999T>C
CM000675.2:g.20188999T>C
NC_000013.10:g.20763138T>C
CM000675.1:g.20763138T>C
NC_000013.9:g.19661138T>C
NG_008358.1:g.8977A>G
NM_004004.5:c.583A>G
ENST00000382844.1:c.583A>G
ENST00000382848.4:c.583A>G

Likely Pathogenic

• Met criteria codes: PP3 PM2 PM3_Strong

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The c.583A>G (p.Met195Val) variant in GJB2 was present in 0.000074% (4/18394, CI 95%) of East Asisan alleles in gnomAD v2.1.1 and was absent from gnomAD v3 (PM2). This variant has been identified in 3 probands with hearing loss in whom another pathogenic or suspected-pathogenic variant was found in trans (PM3_Strong; PMID: 24013081, 20497192, 30146550). It has also been identified in several probands with hearing loss in whom a second variant was not identified (PMID: 23555729, 19366456, 19125024, 27627659, 24507663). The REVEL computational prediction tool produced a score of 0.962, which is above the threshold necessary to apply PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel (PM2, PM3_Strong, PP3).

Met criteria codes

• PP3: REVEL: 0.962 Evolutionarily conserved No predicted splicing impact
• PM2: Present in 0.000074% (4/18394 CI 95%) of East Asian alleles in gnomAD v2.1.1 Absent from gnomAD v3
• PM3_Strong: 3 cases counted (24013081, 30146550, 20497192)

Approved on: 2020-07-15

Published on: 2020-07-15