Submissions for variant NM_000083.3(CLCN1):c.907T>G (p.Trp303Gly)

dbSNP: rs1554436427

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498675	SCV000589857	likely pathogenic	not provided	2016-06-14	criteria provided, single submitter	clinical testing	The W303G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W303G variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Additionally, this substitution occurs at a position that is conserved across species, and missense variants in the same residue (W303R) and in nearby residues (V299L; Y302H; Y302C; R304S; G305E; F306L) have been reported in the Human Gene Mutation Database in association with myotonia congenita (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV001857007	SCV002254520	uncertain significance	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2021-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan with glycine at codon 303 of the CLCN1 protein (p.Trp303Gly). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CLCN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 432168). 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. 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.