Submissions for variant NM_000083.3(CLCN1):c.1931A>G (p.Asp644Gly)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003037042	SCV003195155	uncertain significance	not provided	2022-07-20	criteria provided, single submitter	clinical testing	Reported previously in the compound heterozygous state in a patient with grip/percussion myotonia and variable attacks of muscle stiffness; however, it was unclear if one or both variants were the cause of the symptoms (Jou et al., 2004); Published electrophysiological studies demonstrate that p.(D644G) does not alter channel conductance, but results in a shift of voltage dependence, potentially changing the gating properties of the channel (Lin et al., 2006; Lin et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); 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: 15786415, 19185184, 34790634, 16629771, 18035046, 18220014, 17097617, 15311340)
Labcorp Genetics (formerly Invitae), Labcorp	RCV003777051	SCV004569756	uncertain significance	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 644 of the CLCN1 protein (p.Asp644Gly). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with myotonia congenita (PMID: 15311340). ClinVar contains an entry for this variant (Variation ID: 2136176). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 17097617). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004587412	SCV005077685	uncertain significance	not specified	2024-04-17	criteria provided, single submitter	clinical testing	Variant summary: CLCN1 c.1931A>G (p.Asp644Gly) 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. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 150642 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1931A>G has been reported in the literature in individuals affected with Myotonia congenita (Jou_2004). These report(s) do not provide unequivocal conclusions about association of the variant with Myotonia congenita. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Lin_2008). The following publications have been ascertained in the context of this evaluation (PMID: 15311340, 17097617, 18035046). ClinVar contains an entry for this variant (Variation ID: 2136176). Based on the evidence outlined above, the variant was classified as uncertain significance.