Submissions for variant NM_000166.6(GJB1):c.164C>T (p.Thr55Ile)

dbSNP: rs104894824

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486043	SCV000568357	pathogenic	not provided	2024-07-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate failure to form gap junction-like plaques and intracellular granules in order to traffic proteins to the cell membrane (PMID: 28071741, 12111842); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19369543, 27585976, 14663027, 30196252, 28071741, 12111842, 18236012, 10220155, 11723288, 11271367, 31948496)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851787	SCV002236479	pathogenic	Charcot-Marie-Tooth Neuropathy X	2023-06-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr55 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been observed in individuals with GJB1-related conditions (PMID: 12185164, 12477701), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GJB1 function (PMID: 19369543). 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 not expected to disrupt GJB1 protein function. ClinVar contains an entry for this variant (Variation ID: 10446). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 30196252). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 55 of the GJB1 protein (p.Thr55Ile).
3billion	RCV000011191	SCV004013813	pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010446 / PMID: 10220155). Different missense changes at the same codon (p.Thr55Ala, p.Thr55Arg) have been reported as pathogenic/likely pathogenic with strong evidence (PMID: 12185164, 12477701). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Athena Diagnostics	RCV000486043	SCV004229560	likely pathogenic	not provided	2022-10-19	criteria provided, single submitter	clinical testing	This variant has been identified in at least one individual with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. See PMID: 19369543, 12111842.
OMIM	RCV000011191	SCV000031418	pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1	2001-11-27	no assertion criteria provided	literature only
GeneReviews	RCV000011191	SCV000040499	not provided	Charcot-Marie-Tooth disease X-linked dominant 1		no assertion provided	literature only
Inherited Neuropathy Consortium	RCV000789872	SCV000929257	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only