ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.871G>A (p.Glu291Lys)

gnomAD frequency: 0.00001  dbSNP: rs121912805
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001041229 SCV001204831 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2024-09-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 291 of the CLCN1 protein (p.Glu291Lys). This variant is present in population databases (rs121912805, gnomAD 0.0009%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 8845168, 23739125, 27415035). 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: 17541). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 8845168). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV001781282 SCV002023246 likely pathogenic not provided 2021-10-12 criteria provided, single submitter clinical testing
GeneDx RCV001781282 SCV002575339 pathogenic not provided 2022-04-08 criteria provided, single submitter clinical testing Published functional studies demonstrate the variant results in loss of channel activity in a recessive manner (Pusch et al., 1995); 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: 11933197, 24349310, 34790634, 10508236, 34142127, 11137655, 19185184, 9736777, 8845168, 8533761, 23739125, 35170402, 27415035, 28662944, 32660787)
MGZ Medical Genetics Center RCV000019093 SCV002581039 likely pathogenic Congenital myotonia, autosomal recessive form 2022-07-12 criteria provided, single submitter clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV002468557 SCV002764976 pathogenic Congenital myotonia, autosomal dominant form 2020-11-09 criteria provided, single submitter clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre RCV002468557 SCV004809649 pathogenic Congenital myotonia, autosomal dominant form 2024-04-04 criteria provided, single submitter clinical testing
Athena Diagnostics RCV001781282 SCV005620740 pathogenic not provided 2023-10-25 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 is primarily reported as autosomal recessive myotonia congenita (PMID: 8845168, 8533761, 24349310, 32660787, 34529042, 35170402), however, it has also been reported in individuals with possible autosomal dominant myotonia congenita (PMID: 27415035, 28662944). This variant appears to segregate with autosomal recessive disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 8845168, 34529042) 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.
Fulgent Genetics, Fulgent Genetics RCV001041229 SCV005667221 likely pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2024-04-03 criteria provided, single submitter clinical testing
OMIM RCV000019093 SCV000039381 pathogenic Congenital myotonia, autosomal recessive form 2019-06-21 no assertion criteria provided literature only

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