Variant: NM_004004.6(GJB2):c.563A>G (p.Lys188Arg)

CA387460893

429984 (ClinVar)

Gene: GJB2

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: 4695ee4b-08a2-4fd3-8d4a-f5d1dad3695c

Approved on: 2024-03-28

Published on: 2024-03-28

HGVS expressions

NM_004004.6:c.563A>G
NM_004004.6(GJB2):c.563A>G (p.Lys188Arg)
NC_000013.11:g.20189019T>C
CM000675.2:g.20189019T>C
NC_000013.10:g.20763158T>C
CM000675.1:g.20763158T>C
NC_000013.9:g.19661158T>C
NG_008358.1:g.8957A>G
ENST00000382844.2:c.563A>G
ENST00000382848.5:c.563A>G
ENST00000382844.1:c.563A>G
ENST00000382848.4:c.563A>G
NM_004004.5:c.563A>G

Likely Pathogenic

• Met criteria codes: PM3_Strong PP3 PM2_Supporting

• Not Met criteria codes: PS3

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 NM_004004.6(GJB2):c.563A>G variant in GJB2 is a missense variant predicted to cause substitution of lysine by arginine at amino acid 188 (p.Lys188Arg). The highest population minor allele frequency of the variant is 0.00025% (3/1180000) in the European (non-Finnish) population in gnomAD v.4.0.0 (PM2_Supporting). This variant has been reported in at least three probands with hearing loss (2.5 PM3_Strong points). Two probands were compound heterozygous (one confirmed trans, the other one assumed trans) with the pathogenic c.35delG, p.G12Vfs variant (Clinvar ID: 17004, PMID 17666888, internal data from GeneDx). Another proband was compound heterozygous for the pathogenic variant p.Leu90Pro (ClinVar ID: 17016, University of Minnesota internal data). The REVEL computational prediction analysis tool produced a score of 0.9 meeting PP3. 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: PM2_Supporting, PM3_Strong, PP3 (VCEP specifications version 2; 01.17.2024).

Met criteria codes

• PM3_Strong: 2.5 points from 3 probands 1 proband reported in PMID 17666888 1 proband internal data from University of Minnesota internal data, p.Lys188Arg / p.Leu90Pro, trans phasing inferred from NGS data 1 proband internal data from GeneDx, p.Lys188Arg / c.35delG confirmed in trans
• PP3: Revel score 0.969
• PM2_Supporting: The highest population minor allele frequency of the variant is 0.00025% (3/1180000) in the European (non-Finnish) population in gnomAD v.4.0.0 (PM2_Supporting).

Not Met criteria codes

• PS3: HeLa cells transfected with Cx26 mutant vectors Fluorescence microscopy indicated that cells expressing Lys188Arg showed intracellular fluorescence (similar to S199F, path variant) Patterns indicate ER retention or cytoplasmic aggregation Indicative of mis-trafficking *Not one of our specified functional assays