Submissions for variant NM_000083.3(CLCN1):c.706G>A (p.Val236Ile)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003042499	SCV003329638	likely pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2023-08-07	criteria provided, single submitter	clinical testing	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 currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Val236 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9736777; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 2110756). This variant has not been reported in the literature in individuals affected with CLCN1-related conditions. This variant is present in population databases (rs776173406, gnomAD 0.002%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 236 of the CLCN1 protein (p.Val236Ile).
PreventionGenetics, part of Exact Sciences	RCV004536537	SCV004119925	uncertain significance	CLCN1-related disorder	2023-07-03	criteria provided, single submitter	clinical testing	The CLCN1 c.706G>A variant is predicted to result in the amino acid substitution p.Val236Ile. To our knowledge, this variant has not been previously reported in the literature. This variant is reported in 0.00078% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-143020411-G-A). A different amino acid change at this position (p.Val236Leu) was previously reported in association with autosomal recessive congenita myotonia (Kubisch et al. 1998. PubMed ID: 9736777). Although we suspect CLCN1 c.706G>A (p.Val236Ile) may be pathogenic, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.