Submissions for variant NM_000166.6(GJB1):c.658C>T (p.Arg220Ter)

dbSNP: rs104894814

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000236998	SCV000227040	pathogenic	not provided	2015-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000236998	SCV000292877	pathogenic	not provided	2023-08-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate incomplete channel assembly and significantly reduced currents (Nualart-Marti et al., 2013; Castro et al., 1999); Nonsense variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 8737658, 7477983, 8958325, 21871435, 11571214, 30042657, 25025039, 9401007, 8076700, 24123415, 27228968, 16442804, 10234007, 23587648, 8816997, 9592087, 8162049, 21291455, 28448691, 27844031, 31211173, 30881289, 9364054, 29077882, 34429228, 37284795)
Invitae	RCV000466155	SCV000544782	pathogenic	Charcot-Marie-Tooth Neuropathy X	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg220*) in the GJB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acid(s) of the GJB1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with X-linked dominant Charcot-Marie-Tooth disease (PMID: 7477983, 8162049, 9364054, 21291455). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10435). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GJB1 function (PMID: 8816997, 9364054, 9592087). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000236998	SCV000613499	pathogenic	not provided	2016-01-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000011180	SCV000894502	pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362576	SCV002664676	pathogenic	Inborn genetic diseases	2020-05-21	criteria provided, single submitter	clinical testing	The p.R220* pathogenic mutation (also known as c.658C>T), located in coding exon 1 of the GJB1 gene, results from a C to T substitution at nucleotide position 658. This changes the amino acid from an arginine to a stop codon within coding exon 1. This stop codon occurs at the 3' terminus of GJB1 and is not expected to trigger nonsense-mediated mRNA decay; however, it impacts the last 64 amino acids and removes approximately 23% of the protein. This alteration has been detected in multiple patients and families with X-linked dominant Charcot-Marie-Tooth disease and has been shown to co-segregate with disease (Fairweather N et al. Hum. Mol. Genet., 1994 Jan;3:29-34; Ionasescu VV. Cell Biol. Int., 1998 Nov;22:807-13; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865). Functional studies have demonstrated protein mislocalization and altered gap junction channel activity (Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865; Ressot C et al. J. Neurosci., 1998 Jun;18:4063-75; Carrer A et al. Hum. Mol. Genet., 2018 01;27:80-94). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
OMIM	RCV000011180	SCV000031407	pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1	2012-02-01	no assertion criteria provided	literature only
Inherited Neuropathy Consortium Ii, University Of Miami	RCV000011180	SCV004174708	uncertain significance	Charcot-Marie-Tooth disease X-linked dominant 1	2016-01-06	no assertion criteria provided	literature only
GenomeConnect - Invitae Patient Insights Network	RCV000011180	SCV004228667	not provided	Charcot-Marie-Tooth disease X-linked dominant 1		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 10-28-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.