Submissions for variant NM_004004.6(GJB2):c.146C>T (p.Ala49Val)

gnomAD frequency: 0.00001  dbSNP: rs1057517976

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000412967	SCV000491248	uncertain significance	not specified	2016-12-06	criteria provided, single submitter	clinical testing	The A49V variant in the GJB2 gene has been reported previously in the heterozygous state and also in the presence of another GJB2 variant in Japanese individuals with hearing loss (Ohtsuka et al., 2003; Tsukada et al., 2010), although no family history or other clinical information was reported. The A49V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A49V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, we interpret A49V as a variant of uncertain significance.
Counsyl	RCV000666314	SCV000790586	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2017-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000412967	SCV004020947	likely benign	not specified	2023-06-22	criteria provided, single submitter	clinical testing	Variant summary: GJB2 c.146C>T (p.Ala49Val) results in a non-conservative amino acid change located in the Connexin, N-terminal (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 328300 control chromosomes, predominantly at a frequency of 0.00036 within the Japanese subpopulation (no homozygotes; gnomAD and jMorp databases; Tadaka_2021). The observed variant frequency is approximately 1.1 fold of the estimated maximal expected allele frequency for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (3.4e-04), strongly suggesting that the variant is benign. c.146C>T has been reported in the literature in individuals affected with Hearing Loss (e.g., Ohtsuka_2003, Tsudaka_2010, Nishio_2015), however withouth strong evidence for causality in all cases (e.g., lack of co-segregation and co-occurrence data). These reports do 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: 25788563, 12560944, 20497192, 33179747). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc.	RCV000666314	SCV002086064	uncertain significance	Autosomal recessive nonsyndromic hearing loss 1A	2020-12-07	no assertion criteria provided	clinical testing