Variant: NM_004004.6(GJB2):c.2T>C (p.Met1Thr)

CA6904336

371781 (ClinVar)

Gene: GJB2

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: ee804ee2-6db6-463d-b90d-51e2fd2374f2

HGVS expressions

NM_004004.6:c.2T>C
NM_004004.6(GJB2):c.2T>C (p.Met1Thr)
NC_000013.11:g.20189580A>G
CM000675.2:g.20189580A>G
NC_000013.10:g.20763719A>G
CM000675.1:g.20763719A>G
NC_000013.9:g.19661719A>G
NG_008358.1:g.8396T>C
ENST00000382844.2:c.2T>C
ENST00000382848.5:c.2T>C
ENST00000382844.1:c.2T>C
ENST00000382848.4:c.2T>C
NM_004004.5:c.2T>C

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PM3_Supporting PM5

• Not Met criteria codes: PP3

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

Evidence submitted by expert panel

Hearing Loss VCEP

The c.2T>C (p.Met1Thr) 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, 550716, 551915). This variant has been observed in 0.0074% (8/107882) of the African population in the All of Us database (PM2_Supporting). It was identified in 1 patient with bilateral sensorineural hearing loss who also harbored an assumed trans pathogenic variant (0.5 PM3_Supporting points; Athena Diagnostics internal data, SCV001143666.1). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hearing loss based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PVS1, PM2_Supporting, PM3_Supporting (VCEP specifications version 2; 10.18.2023).

Met criteria codes

• PM2_Supporting: This variant has been observed in 0.0074% (8/107882) of the African population in the All of Us database (PM2_Supporting).
• PVS1: The c.2T>C (p.Met1Thr) 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, 550716, 551915).
• PM3_Supporting: Found with another pathogenic variant (phase unknown) in an infant with bilateral sensorineural hearing loss and no family history of hearing loss (Athena/Quest internal data; SCV001143666.1)
• PM5: The c.1A>G (p.Met1Val) change at this residue has been reported to be pathogenic (ClinVar ID: 44729).

Not Met criteria codes

• PP3: PP3 not applied because PVS1_M was used. (REVEL score 0.894. No mammals in the UCSC database have a substitution at this site, and Alamut indicates this nucleotide is highly conserved. Splicing not predicted to be impacted.)

Approved on: 2024-03-28

Published on: 2024-03-28