ClinVar Miner

Submissions for variant NM_000083.3(CLCN1):c.1450T>C (p.Phe484Leu)

dbSNP: rs1312002847
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001382413 SCV001581167 pathogenic Congenital myotonia, autosomal recessive form; Congenital myotonia, autosomal dominant form 2020-05-21 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect CLCN1 protein function (PMID: 26096614). This variant has been observed in individual(s) with autosomal dominant Thomsen myotonia (PMID: 27639085, 26096614). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 484 of the CLCN1 protein (p.Phe484Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine.
Athena Diagnostics RCV002473287 SCV002771157 pathogenic not provided 2021-10-11 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family. This variant has been reported to be associated with autosomal dominant myotonia congenita (PMID: 23739125, 26096614, 27639085, 28427807, 33573884). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant affects the common-gating function and voltage conductance of the ClC-1 channel (PMID: 26096614, 29500929).
Neuberg Centre For Genomic Medicine, NCGM RCV003339629 SCV004047147 likely pathogenic Congenital myotonia, autosomal dominant form criteria provided, single submitter clinical testing The missense variant c.1450T>C (p.Phe484Leu) in CLCN1 gene has been observed in individual(s) with autosomal dominant Thomsen myotonia (Cassone M et.al.,2017). This variant has been reported to the ClinVar database as Pathogenic. The p.Phe484Leu variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.000003977 is reported in gnomAD. The amino acid Phe at position 484 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by PolyPhen2 and the residue is conserved across species. The amino acid change p.Phe484Leu in CLCN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic .

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