Submissions for variant NM_000166.6(GJB1):c.43C>T (p.Arg15Trp)

dbSNP: rs116840815

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167902	SCV000218550	pathogenic	Charcot-Marie-Tooth Neuropathy X	2024-09-04	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 15 of the GJB1 protein (p.Arg15Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with CMT (PMID: 9099841, 9328258, 9600589, 10521546, 11835375, 21149811). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 21084). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 11325342, 22771394). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000236824	SCV000292871	pathogenic	not provided	2025-02-26	criteria provided, single submitter	clinical testing	Reported in the published literature in association with GJB1-related Charcot-Marie-Tooth disease (PMID: 9328258); Published functional studies demonstrate a damaging effect on channel function (PMID: 11325342, 27025386); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 9099841, 9600589, 11325342, 27025386, 37284795, 35938991, 31069529, 9328258, 35383424)
Athena Diagnostics	RCV000236824	SCV000613486	pathogenic	not provided	2022-12-29	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene and segregates with disease in at least one family. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. In some published literature, this variant is referred to as c.105C>T. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant significantly reduced channel conductance (PMID: 11325342).
Molecular Genetics Laboratory, London Health Sciences Centre	RCV000789234	SCV001336650	pathogenic	Charcot-Marie-Tooth disease		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000020174	SCV005086526	pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Charcot-Marie-Tooth neuropathy, X-linked dominant, 1 (MIM#1302800) (PMID 30042657). (I) 0110 - This gene is associated with X-linked dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance with some females remaining asymptomatic (GeneReviews).(I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0253 - This variant is hemizygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated connexin domain (DECIPHER). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The GJB1 c.44G>A; p.(Arg15Gln) and c.44G>C; p.(Arg15Pro) variants have been previously reported in multiple individuals with Charcot-Marie-Tooth neuropathy (ClinVar; LOVD). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple unrelated individuals with Charcot-Marie-Tooth neuropathy (ClinVar; LOVD). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000020174	SCV005877901	pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1	2024-03-22	criteria provided, single submitter	clinical testing	The GJB1 c.43C>T; p.Arg15Trp variant (rs116840815; ClinVar Variation ID: 217169) is reported in the literature in multiple individuals affected with clinical features consistent with Charcot-Marie-Tooth disease (Nam 2016, Nelis 1996, Nguyen-Le 2022, Yalcouye 2022). Functional analyses of the variant protein show impaired conductance similar to complete knockout of GJB1 (Abrams 2001). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, other variants at this codon (c.44G>A; p.Arg15Gln; c.44G>T; p.Arg15Leu) have been reported in individuals with Charcot-Marie-Tooth disease and are considered pathogenic (Fairweather 1994 and Lu 2017). Based on available information, the p.Arg15Trp variant is considered to be pathogenic. References: Abrams CK et al. Functional alterations in gap junction channels formed by mutant forms of connexin 32: evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease. Brain Res. 2001 May 4;900(1):9-25. PMID: 11325342 Fairweather N et al. Mutations in the connexin 32 gene in X-linked dominant Charcot-Marie-Tooth disease (CMTX1). Hum Mol Genet. 1994 Jan;3(1):29-34. PMID: 8162049. Lu YY et al. Clinical and Genetic Features of Chinese X-linked Charcot-Marie-Tooth Type 1 Disease. Chin Med J (Engl). 2017 May 5;130(9):1049-1054PMID: 28469099 Nam SH et al. Identification of Genetic Causes of Inherited Peripheral Neuropathies by Targeted Gene Panel Sequencing. Mol Cells. 2016 May 31;39(5):382-8. PMID: 27025386 Nelis E et al. Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study. Eur J Hum Genet. 1996;4(1):25-33. PMID: 8800924. Nguyen-Le TH et al. Genotype-phenotype characteristics of Vietnamese patients diagnosed with Charcot-Marie-Tooth disease. Brain Behav. 2022 Sep;12(9):e2744. PMID: 35938991 Yalcouye A et al. GJB1 variants in Charcot-Marie-Tooth disease X-linked type 1 in Mali. J Peripher Nerv Syst. 2022 Jun;27(2):113-119. PMID: 35383424.
GeneReviews	RCV000020174	SCV000040505	not provided	Charcot-Marie-Tooth disease X-linked dominant 1		no assertion provided	literature only
Inherited Neuropathy Consortium	RCV000789234	SCV000928586	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only