Submissions for variant NM_000083.3(CLCN1):c.905A>G (p.Tyr302Cys)

dbSNP: rs1563078716

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000711242	SCV000841575	uncertain significance	not provided	2018-02-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000711242	SCV003830716	uncertain significance	not provided	2021-05-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003768103	SCV004569753	likely pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2023-03-11	criteria provided, single submitter	clinical testing	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.Tr302 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22094069). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 585695). This missense change has been observed in individual(s) with clinical features of CLCN1-related conditions (PMID: 24349310). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 302 of the CLCN1 protein (p.Tyr302Cys).
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences	RCV003768103	SCV005038720	likely pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form		criteria provided, single submitter	research	The c.905A>G (p.(Tyr302Cys)) variant was found in a heterozygous state in 4 Slovak patients with Myotonia congenita, and it was always present in cis with another variant c.1295C>G, p.(Thr432Arg), as already pointed by Skálová et al. 2013 (PMID: 24349310). In two of these patients also other Likely Pathogenic variants were found in the trans position, namely c.2364+2T>C and c.1471+1G>A. The c.905A>G variant is listed as a disease-causing in the HGMD database (CM1313401). GnomAD Exomes Version: 4.0 indicates the frequency of f = 0.00000477.