Submissions for variant NM_000166.6(GJB1):c.14G>T (p.Gly5Val) (rs1064793139)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480735	SCV000565041	uncertain significance	not provided	2017-03-08	criteria provided, single submitter	clinical testing	The G5V variant in the GJB1 gene has been reported previously in an individual with a mitochondrial respiratory chain disease; however, segregation analysis and additional clinical information were not provided (DeBrosse et al., 2016). The G5V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G5V 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. Missense variants in nearby residues (N2K, W3G, W3R, W3S, T4K, Y7C, T8P, T8I, L9W, L9F, S11G) and at the same residue (G5S) have been reported in the Human Gene Mutation Database in association with Charcot-Marie-Tooth syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret G5V as a variant of uncertain significance.
Invitae	RCV000697574	SCV000826194	uncertain significance	Charcot-Marie-Tooth Neuropathy X	2018-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces glycine with valine at codon 5 of the GJB1 protein (p.Gly5Val). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with mitochondrial respiratory chain disease (PMID: 27812541). ClinVar contains an entry for this variant (Variation ID: 418234). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Gly5Ser) has been reported in an individual affected with Charcot-Marie-Tooth disease, type X (PMID: 21291455). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Inherited Neuropathy Consortium	RCV001027491	SCV001190066	likely pathogenic	Charcot-Marie-Tooth disease		no assertion criteria provided	research
Natera, Inc.	RCV001027491	SCV001462641	uncertain significance	Charcot-Marie-Tooth disease	2020-09-16	no assertion criteria provided	clinical testing