Submissions for variant NM_000166.6(GJB1):c.556G>A (p.Glu186Lys)

dbSNP: rs116840821

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654837	SCV000776739	pathogenic	Charcot-Marie-Tooth Neuropathy X	2023-04-22	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects GJB1 function (PMID: 7946361, 9364054, 10848620, 27844031). 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. ClinVar contains an entry for this variant (Variation ID: 21086). This missense change has been observed in individuals with Charcot-Marie-Tooth disease, type IX (PMID: 8266101, 11571214, 12542510, 22243284, 27844031). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 186 of the GJB1 protein (p.Glu186Lys).
CeGaT Center for Human Genetics Tuebingen	RCV001815168	SCV002063330	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000020176	SCV002516475	pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345250	SCV002653038	pathogenic	Inborn genetic diseases	2021-08-27	criteria provided, single submitter	clinical testing	The p.E186K pathogenic mutation (also known as c.556G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 556. The glutamic acid at codon 186 is replaced by lysine, an amino acid with similar properties. This mutation has been detected in multiple unrelated individuals with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) (Liu X et al. Front Neurol, 2020 Jul;11:690; Hsu YH et al. Ann Clin Transl Neurol, 2019 Jun;6:1090-1101; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865; Lu YY et al. Chin Med J (Engl), 2017 May;130:1049-1054; Hong YB et al. J Peripher Nerv Syst, 2017 09;22:172-181; Karadima G et al. Clin Genet, 2011 Nov;80:497-9; Takashima H et al. Acta Neurol Scand, 2003 Jan;107:31-7; Dubourg O et al. Brain, 2001 Oct;124:1958-67). In addition, this mutation has been reported to segregate with CMTX1 in one family (Bergoffen J et al. Science, 1993 Dec;262:2039-42; Fain PR et al. Am J Hum Genet, 1994 Feb;54:229-35). Functional studies indicate that the E186K alteration impairs localization and channel function (Matsuyama W et al. J Hum Genet, 2001;46:307-13; Tsai PC et al. Ann Clin Transl Neurol, 2016 11;3:854-865; Vanslyke JK et al. Mol Biol Cell, 2009 May;20:2451-63; Deschênes SM et al. J Neurosci, 1997 Dec;17:9077-84; VanSlyke JK et al. Mol Biol Cell, 2000 Jun;11:1933-46). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Athena Diagnostics	RCV001815168	SCV002771556	pathogenic	not provided	2021-12-07	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant significantly compromised plasma membrane localization and failed to form functional channels (PMID: 27844031, 7946361, 9364054).
GeneDx	RCV001815168	SCV004170535	pathogenic	not provided	2023-10-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant alters normal GJB1 protein function (PMID: 7946361, 10848620); 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: 22243284, 9364054, 10848620, 8266101, 27844031, 31211173, 10737979, 32376792, 12542510, 7946361)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000020176	SCV004244639	pathogenic	Charcot-Marie-Tooth disease X-linked dominant 1	2023-10-24	criteria provided, single submitter	clinical testing	PS3, PS4, PM2, PP3
GeneReviews	RCV000020176	SCV000040507	not provided	Charcot-Marie-Tooth disease X-linked dominant 1		no assertion provided	literature only
Inherited Neuropathy Consortium	RCV000789812	SCV000929196	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only