Submissions for variant NM_000083.3(CLCN1):c.1231G>T (p.Gly411Cys)

dbSNP: rs756199349

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494058	SCV000582281	uncertain significance	not provided	2017-12-22	criteria provided, single submitter	clinical testing	The G411C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G411C variant is not observed in large population cohorts (Lek et al., 2016). The G411C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with myotonia (Stenson et al., 2014). Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000536398	SCV000636301	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2023-05-08	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 CLCN1 function (PMID: 33013670). 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 CLCN1 protein function. ClinVar contains an entry for this variant (Variation ID: 429659). This missense change has been observed in individual(s) with autosomal recessive myotonic congenita (PMID: 29606556, 33013670; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 411 of the CLCN1 protein (p.Gly411Cys).
CeGaT Center for Human Genetics Tuebingen	RCV000494058	SCV001155293	likely pathogenic	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317242	SCV004020393	likely pathogenic	Congenital myotonia, autosomal recessive form	2023-06-27	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.1231G>T (p.Gly411Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251470 control chromosomes (gnomAD). c.1231G>T has been reported in the literature in compound heterozygous individuals affected with Autosomal Recessive Myotonia Congenita (e.g. Stunnenberg_2018, Altamura_2020). These data indicate that the variant may be associated with disease. When transfected into HEK293 cells, the variant did not properly traffick to the cell surface. When these transfected cells were treated with MG132, the trafficking defect was rescued but cells expressing the variant still failed to produce a chloride current when examined via patch-clamp analysis, indicating the variant produces a non-functional chloride channel (Altamura_2020). The following publications have been ascertained in the context of this evaluation (PMID: 33013670, 29606556). Three ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.