Variant: NM_004004.6(GJB2):c.23C>T (p.Thr8Met)

CA6904332

379889 (ClinVar)

Gene: GJB2

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

UUID: 8756501e-0855-4fe3-9e70-64b3569c122e

Approved on: 2025-01-15

Published on: 2025-03-18

HGVS expressions

NM_004004.6:c.23C>T
NM_004004.6(GJB2):c.23C>T (p.Thr8Met)
NC_000013.11:g.20189559G>A
CM000675.2:g.20189559G>A
NC_000013.10:g.20763698G>A
CM000675.1:g.20763698G>A
NC_000013.9:g.19661698G>A
NG_008358.1:g.8417C>T
ENST00000382844.2:c.23C>T
ENST00000382848.5:c.23C>T
ENST00000382844.1:c.23C>T
ENST00000382848.4:c.23C>T
NM_004004.5:c.23C>T

Uncertain Significance

• Met criteria codes: PM3 PS3_Supporting

• Not Met criteria codes: BA1 PP3 PP2 PM2 BS1 BP4

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.23C>T variant in GJB2 is a missense variant predicted to cause substitution of threonine by methionine at amino acid 8. The filtering allele frequency (the lower threshold of the 95% CI of 75/91084, 1 homozygote) of this variant is 0.06728% in the South Asian chromosomes by gnomAD v4.1.0, which is neither above nor below the thresholds defined by the ClinGen HL EP for autosomal recessive conditions (PM2_Supporting, BS1, and BA1 not met). The computational predictor REVEL gives a score of 0.632, which is neither above nor below the thresholds predicting a damaging or benign impact on GJB2 function. Dual whole cell voltage clamp and dye transfer assays in HeLa cells demonstrated that even though potassium permeability remains the same in the variant, there is a reduction in cationic and large molecules dye transfer compared to WT (PMID:18684989) (PS3_Supporting). This variant has been detected in at least two individuals with autosomal recessive NSHL. One was compound heterozygous for the variant and a pathogenic variant, c.109G>A (p.Val37Ile), with phase unknown (0.5 PM3 points, PMID: 22384008). One individual was homozygous for the variant (0.5 PM3 points, PMID: 31162818) (PM3). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive nonsyndromic genetic hearing loss based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM3, PS3_Supporting (Hearing Loss VCEP specifications version 2; 01/15/2025).

Met criteria codes

• PM3: This variant has been detected in at least two individuals with autosomal recessive NSHL. One was compound heterozygous for the variant and a pathogenic variant, c.109G>A (p.Val37Ile), with phase unknown (0.5 PM3 points, PMID: 22384008). One individual was homozygous for the variant (0.5 PM3 points, PMID: 31162818) (PM3).
• PS3_Supporting: Dual whole cell voltage clamp and dye transfer assays in HeLa cells demonstrated that even though potassium permeability remains the same in the variant, there is a reduction in cationic and large molecules dye transfer compared to WT (PMID:18684989) (PS3_Supporting).

Not Met criteria codes

• BA1: The filtering allele frequency (the lower threshold of the 95% CI of 75/91084, 1 homozygote) of this variant is 0.06728% in the South Asian chromosomes by gnomAD v4.1.0, which is neither above nor below the thresholds defined by the ClinGen HL EP for autosomal recessive conditions (PM2_Supporting, BS1, and BA1 not met).
• PP3: The computational predictor REVEL gives a score of 0.632, which is neither above nor below the thresholds predicting a damaging or benign impact on GJB2 function.
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: The filtering allele frequency (the lower threshold of the 95% CI of 75/91084, 1 homozygote) of this variant is 0.06728% in the South Asian chromosomes by gnomAD v4.1.0, which is neither above nor below the thresholds defined by the ClinGen HL EP for autosomal recessive conditions (PM2_Supporting, BS1, and BA1 not met).
• BS1: The filtering allele frequency (the lower threshold of the 95% CI of 75/91084, 1 homozygote) of this variant is 0.06728% in the South Asian chromosomes by gnomAD v4.1.0, which is neither above nor below the thresholds defined by the ClinGen HL EP for autosomal recessive conditions (PM2_Supporting, BS1, and BA1 not met).
• BP4: The computational predictor REVEL gives a score of 0.632, which is neither above nor below the thresholds predicting a damaging or benign impact on GJB2 function.