ClinVar Miner

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

gnomAD frequency: 0.00003  dbSNP: rs1273330603
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001171543 SCV001334328 uncertain significance Nonsyndromic genetic hearing loss 2020-04-29 reviewed by expert panel curation 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.
GeneDx RCV000523253 SCV000617685 uncertain significance not provided 2020-12-28 criteria provided, single submitter clinical testing Identified in two individuals from a large cohort of patients with hearing loss in published literature (Putcha et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17666888, 25388846, 19081147, 30755392)
Center for Personalized Medicine, Children's Hospital Los Angeles RCV000735348 SCV000854502 likely pathogenic Pulmonary arterial hypertension; Respiratory distress; Neonatal respiratory distress criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003323584 SCV004029843 uncertain significance not specified 2023-07-07 criteria provided, single submitter clinical testing Variant summary: GJB2 c.488T>C (p.Met163Thr) results in a non-conservative amino acid change located in the gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251140 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.488T>C has been reported in the literature as an uninformative genotype (i.e. zygosity not specified) in two alleles from a cohort of individuals undergoing genetic testing for autosomal recessive Non-Syndromic Hearing Loss (Putcha_2007). This report does not provide unequivocal conclusions about association of the variant with Non-Syndromic Hearing Loss. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30755392, 17666888). Three submitters, including the ClinGen Hearing Loss Variant Curation Expert Panel, have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV001829485 SCV002086042 uncertain significance Autosomal recessive nonsyndromic hearing loss 1A 2021-02-12 no assertion criteria provided clinical testing

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