Submissions for variant NM_000083.3(CLCN1):c.1478C>A (p.Ala493Glu)

gnomAD frequency: 0.00001  dbSNP: rs770900468

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000987990	SCV001137533	pathogenic	Congenital myotonia, autosomal recessive form	2019-05-28	criteria provided, single submitter	clinical testing
Invitae	RCV001212828	SCV001384426	pathogenic	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 493 of the CLCN1 protein (p.Ala493Glu). This variant is present in population databases (rs770900468, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 23113340, 24349310). 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: 802379). 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 80%. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 29424939). For these reasons, this variant has been classified as Pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000987990	SCV002499080	pathogenic	Congenital myotonia, autosomal recessive form	2022-02-23	criteria provided, single submitter	clinical testing	PS3, PM1, PM2, PM3_Supporting, PP3
GeneDx	RCV002269327	SCV002552731	pathogenic	not provided	2022-01-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the variant results in loss of protein function (Gaitan-Penas et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23113340, 29424939, 24349310, 32010054, 29606556, 28039888, 28427807, 29050397, 33263785, 34529042, 32117034)
Athena Diagnostics Inc	RCV002269327	SCV002771082	pathogenic	not provided	2022-12-28	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting it is associated with recessive myotonia congenita (PMID: 33263785, 24349310, 23113340), however, it has also been reported in a family with possible autosomal dominant myotonia congenita (PMID: 29424939). Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant decreases CLCN1 membrane expression and channel current (PMID:29424939, 34529042).
Revvity Omics, Revvity	RCV002269327	SCV003830722	uncertain significance	not provided	2021-12-02	criteria provided, single submitter	clinical testing