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.488T>C (p.Met163Thr)

CA387461043

449488 (ClinVar)

Gene: GJB2
Condition: nonsyndromic genetic deafness
Inheritance Mode: Autosomal recessive inheritance
UUID: 87b38ec8-ab7f-45ed-a6dc-0421a0c3c417
Approved on: 2024-11-20
Published on: 2025-01-06

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
ENST00000382844.2:c.488T>C
ENST00000382848.5:c.488T>C
ENST00000382844.1:c.488T>C
ENST00000382848.4:c.488T>C
NM_004004.5:c.488T>C
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Uncertain Significance

Met criteria codes 1
PP3
Not Met criteria codes 2
PM3 PM2

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

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.488T>C (p.Met163Thr) variant in GJB2 is a missense variant predicted to cause a substitution of methionine by threonine at amino acid 163. The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000934 (7/74950) in the African/African-American population, which is higher than the threshold defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (<0.007%), and thus does not meet the criterion for PM2. The REVEL computational prediction analysis tool produced a score of 0.981, which is above the threshold necessary to apply PP3. This variant has been detected in individuals diagnosed with hearing loss (PMID: 17666888), but not in the homozygous state nor in compound heterozygosity with a known pathogenic/likely pathogenic GJB2 variant. The one likely pathogenic entry in ClinVar for this variant, was reported in an infant with an alternative genetic diagnosis explaining respiratory distress and pulmonary hypertension in whom the GJB2 variant was reported at clinician request due to a half-sibling diagnosed with childhood-onset hearing loss (PMID: 30755392, SCV000854502.1). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PP3. (ClinGen Hearing Loss VCEP specifications version 2; 11.20.2024).
Met criteria codes
PP3
The REVEL computational prediction analysis tool produced a score of 0.981, which is above the threshold necessary to apply PP3.
Not Met criteria codes
PM3
This variant has been detected in individuals diagnosed with hearing loss (PMID: 17666888), but not in the homozygous state nor in compound heterozygosity with a known pathogenic/likely pathogenic GJB2 variant.
PM2
The highest population minor allele frequency in gnomAD v4.1.0 is 0.0000934 (7/74950) in the African/African-American population, which is higher than the threshold defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (<0.007%), and thus does not meet the criterion for PM2.
Curation History
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