ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.803C>T (p.Thr268Met) (rs80356687)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497783 SCV000589658 likely pathogenic not provided 2016-03-02 criteria provided, single submitter clinical testing The T268M variant in the CLCN1 gene has been reported previously as a heterozygous variant along with another frameshift variant (phase unknown) in a patient with Becker disease (Skálová et al., 2013) and as a single heterozygous variant in a patient with Becker myotonia; this variant was also present in her mother (Brugnoni et al., 1999). Missense variants in nearby residues (D265E, G270V, G270D, C271R, V273M) have been reported in the Human Gene Mutation Database in association with myotonia congenita (Stenson et al., 2014), supporting the functional importance of this region of the protein. Furthermore, the T268M variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The T268M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, the T268M variant is a strong candidate for a pathogenic variant; however, the possibility it may be a rare benign variant cannot be excluded.
Athena Diagnostics Inc RCV000497783 SCV000612797 pathogenic not provided 2016-03-23 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763168 SCV000893756 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000763168 SCV001584111 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2020-02-24 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 268 of the CLCN1 protein (p.Thr268Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs80356687, ExAC 0.009%). This variant has been observed in individual(s) with autosomal dominant myotonia congenita (PMID: 10533075, 17654559, 21221019, 23113340). It has also been observed to segregate with disease in related individuals. This variant has also been observed in individuals with autosomal recessive myotonia congenita but the association with recessive disease is currently unclear (PMID: 17654559, 23113340, 24349310, 9736066). ClinVar contains an entry for this variant (Variation ID: 21047). This variant has been reported to affect CLCN1 protein function (PMID: 12566541). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000020114 SCV000040434 pathologic Myotonia congenita 2011-04-12 no assertion criteria provided curation Converted during submission to Pathogenic.

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