Submissions for variant NM_000083.3(CLCN1):c.1606G>A (p.Val536Ile)

gnomAD frequency: 0.00006  dbSNP: rs777685454

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000517072	SCV000612766	likely pathogenic	not provided	2016-12-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049002	SCV001213034	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 536 of the CLCN1 protein (p.Val536Ile). This variant is present in population databases (rs777685454, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita and late onset myotonia (PMID: 23152584, 29405036; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 447054). 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%. This variant disrupts the p.Val536 amino acid residue in CLCN1. Other variant(s) that disrupt this residue have been observed in individuals with CLCN1-related conditions (PMID: 24304580), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000517072	SCV003837035	uncertain significance	not provided	2023-12-19	criteria provided, single submitter	clinical testing	Reported in a heterozygous state in an individual with a personal and family history of myotonia congenita (PMID: 28325641); Reported in patients with myotonia who also harbored as second CLCN1 variant, phase unknown (PMID: 23152584, 34529042); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23152584, 31589614, 29405036, 34529042, 24304580, 28325641)
Neuberg Centre For Genomic Medicine, NCGM	RCV003338626	SCV004047996	likely pathogenic	Congenital myotonia, autosomal recessive form		criteria provided, single submitter	clinical testing	The CLCN1 c.1606G>A (p.Val536Ile) variant has been observed in individuals with autosomal recessive myotonia congenita and late onset myotonia (Raheem O et al, Ferese R et al). This p.Val536Ile variant has allele frequency of 0.002829% in the gnomAD and novel (not in any individuals) in 1000 genome database. It has been submitted to ClinVar with varying interpretations: Pathogenic/ Likely Pathogenic. The amino acid Val at position 536 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Val536Ile in CLCN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.