ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.762C>G (p.Cys254Trp)

dbSNP: rs772027125
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000822037 SCV000962817 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2023-11-13 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 254 of the CLCN1 protein (p.Cys254Trp). This variant is present in population databases (rs772027125, gnomAD 0.05%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 31567646, 34790634; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant CLCN1-related conditions (PMID: 31567646; Invitae); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 664036). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCN1 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
The Molecular Genetic and Pathologic Diagnosis Center of Neuromuscular Disorder, Children's Hospital of Fudan University RCV001836901 SCV001786715 likely pathogenic Batten-Turner congenital myopathy 2021-08-15 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000822037 SCV005667215 likely pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2024-06-24 criteria provided, single submitter clinical testing

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