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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_004004.6(GJB2):c.139G>A (p.Glu47Lys)

CA387461835

1806861 (ClinVar)

Gene: GJB2 (HGNC:2706)
Condition: nonsyndromic genetic deafness (MONDO:0019497)
Inheritance Mode: Autosomal recessive inheritance
UUID: 244b0757-c15a-42d5-bba0-fe65208c5339
Approved on: 2026-09-16
Published on: 2026-09-30

HGVS expressions

NM_004004.6:c.139G>A
NM_004004.6(GJB2):c.139G>A (p.Glu47Lys)
NC_000013.11:g.20189443C>T
CM000675.2:g.20189443C>T
NC_000013.10:g.20763582C>T
CM000675.1:g.20763582C>T
NC_000013.9:g.19661582C>T
NG_008358.1:g.8533G>A
ENST00000382844.2:c.139G>A
ENST00000382848.5:c.139G>A
ENST00000382844.1:c.139G>A
ENST00000382848.4:c.139G>A
NM_004004.5:c.139G>A
More

Pathogenic

Met criteria codes 4
PM2_Supporting PM3_Very Strong PS3_Moderate PP3
Not Met criteria codes 16
PVS1 BS2 BS4 BS1 BP4 BP3 BP7 BP5 PS1 PS4 BA1 PP4 PP1 PM5 PM1 PM4

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 2.0

PDF
Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.139G>A variant in GJB2 is a missense variant predicted to cause substitution of glutamic acid by lysine at amino acid 47 (p.Glu47Lys). The highest population minor allele frequency in gnomAD v4.1.1 is 0.00008485% (1/1178590 -European [non-Finnish], PM2_Supporting met). The computational predictor REVEL yields a score of 0.971 (PP3 met). This variant has been detected in at least four individuals with HL, who were compound heterozygous for the variant and pathogenic/likely pathogenic variants del(GJB6-D13S1830), c.299_300delAT (p.His100Argfs), c.235delC (p.Leu79fs), c.269T>C (p.Leu90Pro), confirmed in trans totaling 4.0 points (PM3_VeryStrong; PMIDs: 17666888, 19366456, 20234132, 21366436). Fluorescent dye assay studies in GJB2-expressing HEK293 and HeLa cells showed absent ionic and biochemical coupling (PS3_Moderate; PMIDs: 17146396, 26749107). In summary, based on the current evidence (PM3_VeryStrong, PS3_Moderate, PP3 & PM2_Supporting) this variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic HL based on the ACMG/AMP criteria applied, as specified by the ClinGen HL-VCEP. (ClinGen Hearing Loss VCEP specifications version 2; 09/16/2026).
Met criteria codes
PM2_Supporting
The highest population minor allele frequency in gnomAD v4.1.1 is 0.00008485% (1/1178590 -European [non-Finnish])
PM3_Very Strong
The variant was observed in trans with known pathogenic/likely pathogenic variants in at least four independent affected individuals across published literature (PMIDs: 17666888, 19366456, 20234132, 21366436).
PS3_Moderate
Two independent fluorescent dye assay studies show absent ionic and biochemical coupling (PMIDs: 17146396, 26749107).
PP3
The REVEL yields a score of 0.971.
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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