Submissions for variant NM_000166.6(GJB1):c.622G>A (p.Glu208Lys)

dbSNP: rs1555937270

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000518825	SCV000613495	pathogenic	not provided	2017-01-30	criteria provided, single submitter	clinical testing
Invitae	RCV000805747	SCV000945715	pathogenic	Charcot-Marie-Tooth Neuropathy X	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 208 of the GJB1 protein (p.Glu208Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked Charcot-Marie-Tooth disease (CMT) (PMID: 8162049, 10737979, 14960772, 17646144, 25429913, 28448691). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 447439). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GJB1 function (PMID: 9364054, 9592087, 10848620, 15006706). This variant disrupts the p.Glu208 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14960772). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000518825	SCV001500644	pathogenic	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002367715	SCV002659810	pathogenic	Inborn genetic diseases	2020-11-10	criteria provided, single submitter	clinical testing	The p.E208K pathogenic mutation (also known as c.622G>A), located in coding exon 1 of the GJB1 gene, results from a G to A substitution at nucleotide position 622. The glutamic acid at codon 208 is replaced by lysine, an amino acid with similar properties. This alteration has been detected in individuals with Charcot-Marie-Tooth neuropathy and has been reported to segregate with disease in families (Fairweather N et al. Hum Mol Genet, 1994 Jan;3:29-34; Feng SY et al. J Clin Neurol, 2018 Apr;14:261-263). Additionally, studies have shown that this alteration affects the function of the GJB1 protein (Deschênes SM et al. J Neurosci, 1997 Dec;17:9077-84; Ressot C et al. J Neurosci, 1998 Jun;18:4063-75; VanSlyke JK et al. Mol Biol Cell, 2000 Jun;11:1933-46; Wang HL et al. Neurobiol Dis, 2004 Mar;15:361-70). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000518825	SCV003805347	pathogenic	not provided	2023-01-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate the variant results in impaired intracelluar trafficking of the protein to the plasma membrane (Deschenes et al., 1997; Wang et al., 2004); Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31372974, 32047472, 9592087, 9364054, 10848620, 17646144, 26454100, 15006706, 29629536, 27549087, 8162049, 14960772)
Inherited Neuropathy Consortium	RCV000789848	SCV000929233	uncertain significance	Charcot-Marie-Tooth disease		no assertion criteria provided	literature only