ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.2551G>A (p.Val851Met)

gnomAD frequency: 0.00004  dbSNP: rs749205522
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000706396 SCV000835442 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2024-01-05 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 851 of the CLCN1 protein (p.Val851Met). This variant is present in population databases (rs749205522, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 22094069, 23739125, 29935101, 32117024). 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 myotonia congenita (PMID: 29935101, 32117024); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 582345). 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 affects CLCN1 function (PMID: 29935101). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV001289382 SCV001477152 likely pathogenic not provided 2019-09-27 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
DASA RCV001824155 SCV002073762 likely pathogenic Congenital myotonia, autosomal dominant form 2022-02-05 criteria provided, single submitter clinical testing The c.2551G>A;p.(Val851Met) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 582345; PMID: 32117024; 29935101; 22094069; 23739125; 29935101) - PS4. The variant is present at low allele frequencies population databases (rs749205522 – gnomAD 0.0003944%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 32117024) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. The variant was observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID: 32117024) BP2. In summary, the currently available evidence indicates that the variant is likely pathogenic.

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