Submissions for variant NM_000083.3(CLCN1):c.1679T>C (p.Met560Thr)

dbSNP: rs1269268607

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001203792	SCV001374969	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-04-06	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 560 of the CLCN1 protein (p.Met560Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with myotonia congenita (PMID: 21045501, 23603549, 24349310, 25749817, 26260254). 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. ClinVar contains an entry for this variant (Variation ID: 935242). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002245868	SCV002512917	pathogenic	not provided	2022-02-11	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that p.(M560T) results in shifted voltage dependence compared to wildtype which is suggestive of loss of function (Suetterlin et al., 2021); 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: 32660787, 24349310, 28325641, 23091531, 21045501, 23603549, 23113340, 26260254, 34790634, 34675092, 34529042, 25749817)
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV002267634	SCV002549780	likely pathogenic	Congenital myotonia, autosomal dominant form	2022-04-06	no assertion criteria provided	research
Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	RCV002267633	SCV002549787	likely pathogenic	Congenital myotonia, autosomal recessive form	2022-04-06	no assertion criteria provided	research