ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1238T>G (p.Phe413Cys)

gnomAD frequency: 0.00028  dbSNP: rs121912799
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Courtagen Diagnostics Laboratory, Courtagen Life Sciences RCV000184008 SCV000236506 pathogenic Congenital myotonia, autosomal dominant form 2014-03-27 criteria provided, single submitter clinical testing
GeneDx RCV000346725 SCV000329299 pathogenic not provided 2023-10-27 criteria provided, single submitter clinical testing Published functional studies suggest F413C results in reduced transport of the CLCN1 protein out of the endoplasmic reticulum (PMID: 17990293); 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: 1379744, 29790872, 23739125, 10690989, 7981750, 8301644, 9040760, 7951242, 11840191, 31589614, 12390967, 33263785, 18807109, 17932099, 34790634, 32670189, 18337730, 34758253, 34529042, 8533761, 17990293, 21204798)
Eurofins Ntd Llc (ga) RCV000346725 SCV000331890 pathogenic not provided 2016-06-28 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000184008 SCV000584084 pathogenic Congenital myotonia, autosomal dominant form 2016-10-13 criteria provided, single submitter research
Athena Diagnostics Inc RCV000346725 SCV000612755 pathogenic not provided 2022-06-03 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families with autosomal recessive myotonia congenita (PMID: 8533761, 21204798), however, it has also been reported in individuals with possible autosomal dominant myotonia congenita (PMID: 11840191, 17932099). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant reduces protein transport from the endoplasmic reticulum (PMID: 17990293). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
Invitae RCV000638232 SCV000759718 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 413 of the CLCN1 protein (p.Phe413Cys). This variant is present in population databases (rs121912799, gnomAD 0.2%). This missense change has been observed in individuals with autosomal recessive myotonia congenita (PMID: 1379744, 8533761, 11840191, 18337730, 23739125). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17531). 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%. Experimental studies have shown that this missense change affects CLCN1 function (PMID: 10690989, 17990293). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen RCV000346725 SCV001248207 pathogenic not provided 2017-05-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000346725 SCV001715971 pathogenic not provided 2020-02-28 criteria provided, single submitter clinical testing PS3, PS4_moderate, PM3, PP1, PP3
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino RCV001548747 SCV001763566 pathogenic Tip-toe gait 2020-08-18 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000346725 SCV002017365 pathogenic not provided 2023-05-18 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV002291268 SCV002583812 pathogenic CLCN1-related disorder 2022-08-07 criteria provided, single submitter clinical testing PS3 PP3 PP1 PS4_Moderate PM3
OMIM RCV000019083 SCV000039371 pathogenic Congenital myotonia, autosomal recessive form 1993-11-01 no assertion criteria provided literature only
Genomics England Pilot Project, Genomics England RCV000184008 SCV001760194 likely pathogenic Congenital myotonia, autosomal dominant form no assertion criteria provided clinical testing

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