Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_004004.5(GJB2):c.107T>C (p.Leu36Pro)

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CA172208

158604 (ClinVar)

Gene: GJB2

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: e657ec2a-42b6-42fd-94ab-817fd6805f5d

Approved on: 2019-04-29

Published on: 2019-07-17

HGVS expressions

NM_004004.5:c.107T>C

NM_004004.5(GJB2):c.107T>C (p.Leu36Pro)

NC_000013.11:g.20189475A>G

CM000675.2:g.20189475A>G

NC_000013.10:g.20763614A>G

CM000675.1:g.20763614A>G

NC_000013.9:g.19661614A>G

NG_008358.1:g.8501T>C

ENST00000382844.2:c.107T>C

ENST00000382848.5:c.107T>C

ENST00000382844.1:c.107T>C

ENST00000382848.4:c.107T>C

NM_004004.6:c.107T>C

Uncertain Significance

PP3 PM3 PM2_Supporting

BS1 BP4 BP1 BP7 PS1 BA1 PP2 PM5 PVS1

Evidence Links 3

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The allele frequency of the p.Leu36Pro variant in the GJB2 gene is 0.01% (2/19954) of East Asian chromosomes by gnomAD, 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). The REVEL computational prediction analysis tool produced a score of 0.945, which is above the threshold necessary to apply PP3. This variant has been detected in one patient with hearing loss in trans with 35delG (PM3; PMID:16125251). The variant has also been reported in three individuals with no pathogenic variant found in trans (PMIDs: 17666888, 26043044). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PP3, PM3.

PP3

REVEL score in 0.945

PM3

The p.Leu36Pro variant is found in trans with 35delG in one African proband.

The p.Leu36Pro variant was found in trans with a c.79G>A (p.Val27Ile) and a c.341A>G (p.Glu114Gly) variant, in a Han Chinese hearing loss patient. Both variants found in trans are at high frequency in gnomAD and have been repeatedly reported as Benign in ClinVar. PubMed:26043044

Of 65 nonsyndromic pediatric cochlear implant patients with severe to profound hearing loss, the p.L36P variant was found in one African proband in trans with the 35delG variant. Four total African ethnicity probands were included in this study. PubMed:16125251

The p.L36P variant was found in two North American individuals with unspecified hearing loss. No variant was identified in trans PubMed:17666888

PM2_Supporting

The variant is present in 2/19954 (0.01%) East Asian alleles in gnomAD.

BS1