ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1366G>A (p.Val456Ile)

gnomAD frequency: 0.00001  dbSNP: rs922819878
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001773931 SCV001992162 uncertain significance not provided 2019-04-24 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp RCV003771939 SCV004572511 uncertain significance Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2024-01-17 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 456 of the CLCN1 protein (p.Val456Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CLCN1-related conditions (PMID: 34529042). ClinVar contains an entry for this variant (Variation ID: 1305221). 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. Experimental studies have shown that this missense change does not substantially affect CLCN1 function (PMID: 34529042). 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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