ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.929C>T (p.Thr310Met)

gnomAD frequency: 0.00001  dbSNP: rs80356691
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000516849 SCV000612806 pathogenic not provided 2016-05-03 criteria provided, single submitter clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV001823101 SCV002073049 pathogenic Congenital myotonia, autosomal recessive form criteria provided, single submitter clinical testing The missense variant p.T310M in CLCN1 (NM_000083.3) has been reported both in autosomal dominant as well as recessive myotonia congenita (Bernard G et al; Wu Fen-Fen et al).Functional studies suggest a damaging effect by affecting the opening rate (Duffield M et al). It has been submitted to ClinVar as Pathogenic. It is novel (not in any individuals) in gnomAD Exomes and 1000 Genome. The p.T310M missense variant is predicted to be damaging by both SIFT and PolyPhen2 and the residue is conserved across species. For these reasons, this variant has been classified as Pathogenic.
Invitae RCV002514123 SCV003264555 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2024-01-14 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 310 of the CLCN1 protein (p.Thr310Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant myotonia congenita (PMID: 12390967, 15311340, 19949657; Invitae). This variant has been reported in individual(s) with autosomal recessive myotonia congenita (PMID: 18263754); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 21051). 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: 12390967, 12566541). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000020119 SCV000040439 not provided Batten-Turner congenital myopathy no assertion provided literature only Associated with autosomal recessive and autosomal dominant mode of inheritance

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