Submissions for variant NM_000166.6(GJB1):c.223C>T (p.Arg75Trp)

dbSNP: rs116840819

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236563	SCV000293446	pathogenic	not provided	2023-10-25	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on the gene product (PMID: 12460545, 23209285); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Different missense changes at this residue (R75Q) and (R75P) have been reported in the Human Gene Mutation Database and in published literature (PMID: 8829637, 9272161, 23209285, 12460545, 32489946, 32399692; HGMD); 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, 9361298, 14663027, 12460545, 12402337, 17100997, 23209285, 30373780, 29095325, 32941234, 32399692, 9272161, 10732813, 8829637, 32489946)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654844	SCV000776746	pathogenic	Charcot-Marie-Tooth Neuropathy X	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 75 of the GJB1 protein (p.Arg75Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Charcot-Marie-Tooth disease (CMT) (PMID: 9272161, 10732813, 12402337, 14663027, 15719046, 17100997). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21082). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 12460545, 19369543, 23209285). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000020172	SCV001158504	pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1	2019-06-11	criteria provided, single submitter	clinical testing	The GJB1 c.223C>T; p.Arg75Trp variant (rs116840819) is reported frequently in the literature in individuals affected with X-linked Charcot-Marie-Tooth neuropathy (select references: Silander 1997, Zhang 2005, Parissis 2017, and Bacquet 2018). Functional analyses of the variant protein in cell culture and transgenic mice show that the p.Arg75Trp variant causes defects in GJB1 protein function consistent with known CMT disease mechanisms (Sargiannidou 2009, Abrams 2013). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic.
Athena Diagnostics	RCV000236563	SCV001880849	pathogenic	not provided	2023-08-23	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals 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. Studies showed defective protein activity and transgenic mice with a demyelinating neuropathy (PMID: 12460545, 19369543, 23209285, 28334782).
MGZ Medical Genetics Center	RCV000020172	SCV002580735	pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1	2022-01-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002426512	SCV002727953	likely pathogenic	Inborn genetic diseases	2021-10-21	criteria provided, single submitter	clinical testing	The p.R75W variant (also known as c.223C>T), located in coding exon 1 of the GJB1 gene, results from a C to T substitution at nucleotide position 223. The arginine at codon 75 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in the hemizygous state in multiple unrelated males with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1), as well as in heterozygous carrier females with mild symptoms (Vogt B et al. J Neurol, 2020 Sep;267:2648-2654; Silander K et al. Hum Genet, 1997 Sep;100:391-7; Zhang RX et al. Beijing Da Xue Xue Bao Yi Xue Ban, 2005 Feb;37:68-71; Parissis D et al. Neurologist, 2017 Nov;22:234-236). Functional studies indicate this alteration impairs gap junction formation and transgenic mice expressing this alteration recapitulate the phenotype (Kagiava A et al. Hum Mol Genet, 2018 04;27:1460-1473; Kyriakoudi S et al. Hum Mol Genet, 2017 05;26:1622-1633; Abrams CK et al. J Biol Chem, 2013 Feb;288:3609-19; Sargiannidou I et al. J Neurosci, 2009 Apr;29:4736-49). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000236563	SCV005198025	pathogenic	not provided	2024-03-19	criteria provided, single submitter	clinical testing
GeneReviews	RCV000020172	SCV000040501	not provided	Charcot-Marie-Tooth disease X-linked dominant 1		no assertion provided	literature only
Inherited Neuropathy Consortium	RCV000789309	SCV000928662	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only