ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.652G>A (p.Ala218Thr) (rs189963844)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487022 SCV000568784 uncertain significance not provided 2016-08-02 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CLCN1 gene. The A218T variant has been reported in the heterozygous state in an individual with Thomsen disease; however, it did not segregate with Thomsen disease in the affected father and functional characterization of the variant was not performed (de Diego et al., 1999). The A218T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations, and it was not observed with any significant frequency in the 1000 Genomes Project. The A218T 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 where amino acids with similar properties to Alanine are tolerated across species. Additionally, a missense variant in a nearby residue (V217D) has been reported in the Human Gene Mutation Database in association with a CLCN1-related disorder (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000803459 SCV000943331 uncertain significance Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 218 of the CLCN1 protein (p.Ala218Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs189963844, ExAC 0.03%). This variant has been observed in an individual affected with myotonia congenita (PMID: 10525982). ClinVar contains an entry for this variant (Variation ID: 420147). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The observation of one or more missense substitutions at this codon (p.Ala218Val) in affected individuals suggests that this may be a clinically significant residue (PMID: 22094069). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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