Variant: NM_004004.6(GJB2):c.110T>C (p.Val37Ala)

CA6904317

449490 (ClinVar)

Gene: GJB2

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: 1d8c5ad9-8453-4ae4-8c22-1b4c7b044189

HGVS expressions

NM_004004.6:c.110T>C
NM_004004.6(GJB2):c.110T>C (p.Val37Ala)
NM_004004.5:c.110T>C
ENST00000382844.1:c.110T>C
ENST00000382848.4:c.110T>C
NC_000013.11:g.20189472A>G
CM000675.2:g.20189472A>G
NC_000013.10:g.20763611A>G
CM000675.1:g.20763611A>G
NC_000013.9:g.19661611A>G
NG_008358.1:g.8504T>C

Likely Pathogenic

• Met criteria codes: PM2_Supporting PP3 PM3 PM5

• Not Met criteria codes: PS3

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Evidence submitted by expert panel

Hearing Loss VCEP

The allele frequency of the p.Val37Ala variant in the GJB2 gene is 0.04% (13/35428) of Latino chromosomes by gnomAD v2.1.1, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). This variant has been identified in 3 heterozygous individuals with hearing loss who did not harbor a second variant in GJB2 (PMID 21287563, PMID 17666888, PMID 15365987), but has also been detected in 1 patient with hearing loss in trans with a pathogenic variant (PM3; Partners LMM internal data SCV000967620.2). The REVEL computational prediction analysis tool produced a score of 0.675, which rounded up to 0.7 is above the threshold necessary to apply PP3 (PP3). A different pathogenic missense variant (p.Val37Ile) has been previously identified at this codon of GJB2 which may indicate that this residue is critical to the function of the protein (PM5; p.Val37Ile ClinVar Variation ID 17023, PMID 31160754). 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 (PM3, PM5, PM2_Supporting, PP3).

Met criteria codes

• PM2_Supporting: The variant is found in 13/35428 (0.04%) of Latino alleles in gnomAD version 2.1.1. This is low enough to meet the threshold for PM2_Supporting (<0.07%)
• PP3: The REVEL score is 0.675, which is lower than our pathogenic cutoff of 0.7. However, the HL VCEP experts have voted to round up and apply PP3.
• PM3: While there are many heterozygous cases that weren't counted, PM3 is applied because the variant was identified by LMM in one individual with hearing loss who was compound het for the c.167delT variant in GJB2. Phase was confirmed.
• PM5: The p.Val37Ile variant is classified as Pathogenic by the Hearing Loss VCEP. There is a second variant that is classified as LP by Partners LMM (p.Val37Phe). However, there is only one reported individual and PM5 with V37I is used to get it to its LP classification. For that reason, I didn't upgrade PM5.

Not Met criteria codes

• PS3: Bioinformatic analysis was used to predict the effect of the p.Val37Ala variant on GJB2 and molecular modeling determined that there may be a loss of protein structure. However, because no in vitro or in vivo experiments were done, this was not counted towards PS3.

Approved on: 2020-07-28

Published on: 2020-07-28