Submissions for variant NM_000083.3(CLCN1):c.2795C>T (p.Pro932Leu) (rs80356706)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478940	SCV000568787	uncertain significance	not provided	2018-12-21	criteria provided, single submitter	clinical testing	The P932L variant has been reported to segregate with disease in a family with a myotonic disorder. The most severely affected family members harbored the P932L variant as well as a frameshift variant on the other allele (Nagamitsu et al., 2000). P932L was also reported in an individual with myotonia congenita who was heterozygous for two additioanl variants in the CLCN1 gene (Brugnoni et al., 2013). Functional studies demonstrated that P932L resulted in nearly wildtype chloride currents (Simpson et al., 2004). P932L was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project; however, the 1000 Genomes Project reports P932L was observed in 4/1132 (0.3%) alleles from individuals of African background. The P932L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals; although, Leucine has been observed at this position in evolution. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae	RCV000638250	SCV000759736	uncertain significance	Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form	2018-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 932 of the CLCN1 protein (p.Pro932Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs80356706, ExAC 0.1%). This variant has been reported to segregate with myotonia congenita in a single family and the variant was reported in combination with another CLCN1 variant in 2 of the family members with a more severe phenotype; however, a myotonic phenotype was also observed in the individuals who carried this variant only (PMID: 111113225). This variant has also been reported in combination with two other variants in an individual affected with myotonia congenita (PMID: 23739125). ClinVar contains an entry for this variant (Variation ID: 17533). Experimental studies have shown that this missense change reduces slightly the surface expression of the channel without changing its voltage dependence of gating, and chloride currents in cells expressing p.P932L were not significantly different from those of cells expressing wild-type (PMID: 17107341, 15241802). 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.
OMIM	RCV000019085	SCV000039373	pathogenic	Congenital myotonia, autosomal recessive form	2000-12-12	no assertion criteria provided	literature only
GeneReviews	RCV000020108	SCV000040428	pathologic	Myotonia congenita	2011-04-12	no assertion criteria provided	curation	Converted during submission to Pathogenic.