Evidence Repository
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.1A>T (p.Met1Leu)

CA387462311

550716 (ClinVar)

Gene: GJB2
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 0e37ea71-2f4d-4d10-80f4-7d50cd0347b7

HGVS expressions

NM_004004.6:c.1A>T
NM_004004.6(GJB2):c.1A>T (p.Met1Leu)
NC_000013.11:g.20189581T>A
CM000675.2:g.20189581T>A
NC_000013.10:g.20763720T>A
CM000675.1:g.20763720T>A
NC_000013.9:g.19661720T>A
NG_008358.1:g.8395A>T
ENST00000382844.2:c.1A>T
ENST00000382848.5:c.1A>T
ENST00000382844.1:c.1A>T
ENST00000382848.4:c.1A>T
NM_004004.5:c.1A>T

Likely Pathogenic

Met criteria codes 2
PVS1 PM2_Supporting

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

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The 1A>T (p.Met1Leu) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 44729, 2070085, 551915, 371781). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting (VCEP specifications version 2; 10.18.2023).
Met criteria codes
PVS1
The 1A>T (p.Met1Leu) variant in GJB2 may cause a truncated or absent protein by altering the start codon of the coding sequence and is predicted to lead to the omission of a critical region of the protein. There have been multiple pathogenic variants observed in the region between this site and the next expected start codon (PVS1; ClinVar Variation IDs: 21387, 188758). There are also multiple pathogenic/likely pathogenic start-loss variants at this position which may indicate that this residue is critical to the function of the protein (ClinVar Variation IDs: 44729, 2070085, 551915, 371781).
PM2_Supporting
This variant is absent from gnomAD v2.1.1
Approved on: 2024-03-28
Published on: 2024-03-28
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