ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.2795C>T (p.Pro932Leu)

gnomAD frequency: 0.00035  dbSNP: rs80356706
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478940 SCV000568787 uncertain significance not provided 2020-05-28 criteria provided, single submitter clinical testing Functional studies indicate P932L results in reduced surface expression of CLCN1 protein (Macias et al., 2007); Functional studies demonstrate that P932L results in nearly wildtype chloride currents (Simpson et al., 2004); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19917643, 27653901, 18263754, 11933197, 15241802, 11113225, 12566541, 15786415, 23739125, 15311340, 29935101, 17107341, 32117034)
Labcorp Genetics (formerly Invitae), Labcorp RCV000638250 SCV000759736 uncertain significance Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2023-12-28 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 932 of the CLCN1 protein (p.Pro932Leu). This variant is present in population databases (rs80356706, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal recessive myotonia congenita (PMID: 11113225, 23739125). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17533). 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 not expected to disrupt CLCN1 protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CLCN1 function (PMID: 15241802, 17107341). 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.
Revvity Omics, Revvity RCV000478940 SCV003832360 uncertain significance not provided 2022-07-13 criteria provided, single submitter clinical testing
OMIM RCV000019085 SCV000039373 pathogenic Congenital myotonia, autosomal recessive form 2000-12-12 no assertion criteria provided literature only
GeneReviews RCV000020108 SCV000040428 not provided Batten-Turner congenital myopathy no assertion provided literature only

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