Submissions for variant NM_000166.6(GJB1):c.704T>G (p.Phe235Cys)

gnomAD frequency: 0.00295  dbSNP: rs104894825

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000344288	SCV000342948	benign	not specified	2016-07-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000011195	SCV000482715	likely benign	Charcot-Marie-Tooth disease X-linked dominant 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV001711068	SCV000520914	likely benign	not provided	2020-07-02	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23871722, 22771394, 15852376, 21291455, 27066513, 12951564, 27228968, 9361298, 30340945)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467010	SCV000556953	benign	Charcot-Marie-Tooth Neuropathy X	2025-01-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000011195	SCV001141917	likely benign	Charcot-Marie-Tooth disease X-linked dominant 1	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002362577	SCV002662103	uncertain significance	Inborn genetic diseases	2014-07-25	criteria provided, single submitter	clinical testing	The p.F235C variant (also known as c.704T>G), located in coding exon 1 of the GJB1 gene, results from a T to G substitution at nucleotide position 704. The phenylalanine at codon 235 is replaced by cysteine, an amino acid with highly dissimilar properties.This variant, which occurs in the C-terminal domain, is purported to result in a gain of function activity and is associated with a severe and early onset form of Charcot-Marie-Tooth disease (Bone, LJ et al. Neurobiol Dis 1997;4:221-30, Kim, Y et al. Clin Genet 2012;81:142-149, Liang, GS et al. Ann Neurol 2005;57:749-754, Lin, GS et al. Ann NY Acad Sci 1999;883:481-4). This variant was previously reported in the SNPDatabase as rs104894825. Based on data from the 1000 Genomes Project, the G allele has an overall frequency of approximately 0% (0/503) total male alleles studied. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.16% (4/2443) total male alleles studied, having been observed in 0.7% (4/571) African American male alleles. This amino acid position is conserved in available mammalian species, but is not conserved from chicken down. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence for this variant is conflicting at this time, the clinical significance of this variant remains unclear.
Breakthrough Genomics, Breakthrough Genomics	RCV001711068	SCV005210600	likely benign	not provided		criteria provided, single submitter	not provided
Athena Diagnostics	RCV000344288	SCV005622219	benign	not specified	2024-06-25	criteria provided, single submitter	clinical testing
OMIM	RCV000011195	SCV000031422	pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1	2005-05-01	no assertion criteria provided	literature only
GeneReviews	RCV000011195	SCV000040510	not provided	Charcot-Marie-Tooth disease X-linked dominant 1		no assertion provided	literature only
Natera, Inc.	RCV001271691	SCV001453016	benign	Charcot-Marie-Tooth disease	2020-06-28	no assertion criteria provided	clinical testing