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_004004.6(GJB2):c.488T>C (p.Met163Thr)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA387461043

449488 (ClinVar)

Gene: GJB2

Condition: nonsyndromic genetic deafness

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 87b38ec8-ab7f-45ed-a6dc-0421a0c3c417

Approved on: 2020-04-29

Published on: 2020-04-30

HGVS expressions

NM_004004.6:c.488T>C

NM_004004.6(GJB2):c.488T>C (p.Met163Thr)

NC_000013.11:g.20189094A>G

CM000675.2:g.20189094A>G

NC_000013.10:g.20763233A>G

CM000675.1:g.20763233A>G

NC_000013.9:g.19661233A>G

NG_008358.1:g.8882T>C

NM_004004.5:c.488T>C

ENST00000382844.1:c.488T>C

ENST00000382848.4:c.488T>C

Uncertain Significance

PP3 PM2

Evidence Links 0

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The c.488T>C (p.Met163Thr) variant in GJB2 is present in 0.0115% (1/8710) of African chromosomes in gnomAD 2.1.1, which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The REVEL computational prediction analysis tool produced a score of 0.981, which is above the threshold necessary to apply PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PP3.

PP3

REVEL score is 0.981. No splicing impact predicted by splicing predictors in Alamut, which includes MaxEntScan. The Met163 residue is highly conserved across all vertebrates in the UCSC browser except for "Lizard" which has an Ile at this position.

PM2

This variant is present in 0.0115% (1/8710) of African chromosomes in gnomAD v2.1.1 and in 0.0095% (4/42060) of African chromosomes in gnomAD v3.

Curation History

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