Submissions for variant NM_000166.6(GJB1):c.64C>T (p.Arg22Ter)

dbSNP: rs1555937020

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000516443	SCV000613498	pathogenic	not provided	2017-03-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763633	SCV000894501	pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000796941	SCV000936476	pathogenic	Charcot-Marie-Tooth Neuropathy X	2022-10-18	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 447441). This premature translational stop signal has been observed in individual(s) with Charcot-Marie-Tooth disease type X (CMTX) (PMID: 8004109, 9401007, 11571214, 21692908). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg22*) in the GJB1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 262 amino acid(s) of the GJB1 protein. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory, London Health Sciences Centre	RCV000789221	SCV001336648	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
GeneDx	RCV000516443	SCV001823793	pathogenic	not provided	2019-04-11	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31948496, 27228968, 8698335, 21692908, 18379723, 9401007, 21291455, 28768847, 24123415, 8004109)
CeGaT Center for Human Genetics Tuebingen	RCV000516443	SCV002585130	pathogenic	not provided	2022-09-01	criteria provided, single submitter	clinical testing	GJB1: PVS1:Strong, PM2, PS4:Moderate, PP1, PP4
Ambry Genetics	RCV002367716	SCV002659174	pathogenic	Inborn genetic diseases	2023-11-01	criteria provided, single submitter	clinical testing	The c.64C>T (p.R22*) alteration, located in exon 2 (coding exon 1) of the GJB1 gene, consists of a C to T substitution at nucleotide position 64. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 22. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been detected in several individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) (Ionasescu, 1994; Rouger, 1997; Mandich, 2008; Dubourg, 2001). Based on the available evidence, this alteration is classified as pathogenic.
Neurogenomics Lab, Neuroscience Institute, University Of Cape Town	RCV000763633	SCV003930347	pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1	2024-05-22	criteria provided, single submitter	research	PM2_supporting: This variant is absent from gnomAD v4.0 (adequate coverage >20x confirmed) and an internal database of 1074 control alleles. PM1 met: variant occurs in the N-terminus connexin domain together with other pathogenic variants. PS4 met: variant identified in = 10 unrelated probands with consistent phenotype for disorder. PVS1 met: null variant (nonsense or frameshift variant, predicted to undergo NMD, exon is present in biologically-relevant transcript) in a gene where LOF is a known mechanism of disease. PP1 met: variant segregates with 3 informative meioses in 1 family (PMID: 8698335). Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/.
Inherited Neuropathy Consortium	RCV000789221	SCV000928573	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only
Inherited Neuropathy Consortium Ii, University Of Miami	RCV000763633	SCV004174718	uncertain significance	Charcot-Marie-Tooth disease X-linked dominant 1	2016-01-06	no assertion criteria provided	literature only