Submissions for variant NM_000166.6(GJB1):c.52A>T (p.Thr18Ser)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002979199	SCV003287899	pathogenic	Charcot-Marie-Tooth Neuropathy X	2023-10-03	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 18 of the GJB1 protein (p.Thr18Ser). This variant is not present in population databases (gnomAD no frequency). A different variant (c.53C>G) giving rise to the same protein effect has been determined to be pathogenic (Invitae). This suggests that this variant is also likely to be causative of disease. ClinVar contains an entry for this variant (Variation ID: 2076285). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GJB1 protein function. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526214	SCV005040087	uncertain significance	not specified	2024-03-07	criteria provided, single submitter	clinical testing	Variant summary: GJB1 c.52A>T (p.Thr18Ser) results in a conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183023 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.52A>T in individuals affected with Charcot-Marie-Tooth disease X-linked dominant 1 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains a Pathogenic entry for this variant that cites an indirect evidence of a different de-novo variant resulting in the same amino acid change (Variation ID: 2076285). Based on the evidence outlined above, the variant was classified as uncertain significance.