Submissions for variant NM_000069.3(CACNA1S):c.766A>G (p.Ile256Val)

gnomAD frequency: 0.00001  dbSNP: rs190152688

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001101988	SCV001258634	uncertain significance	Hypokalemic periodic paralysis, type 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856390	SCV002209889	benign	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5	2023-07-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002489745	SCV002777399	uncertain significance	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5; Thyrotoxic periodic paralysis, susceptibility to, 1	2022-03-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317431	SCV004021246	benign	not specified	2023-06-30	criteria provided, single submitter	clinical testing	Variant summary: CACNA1S c.766A>G (p.Ile256Val) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251136 control chromosomes (gnomAD), predominantly at a frequency of 0.001 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 800 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1S causing Hypokalemic Periodic Paralysis (1.3e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.766A>G in individuals affected with Hypokalemic Periodic Paralysis and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters have assessed the variant since 2014: two classified the variant as uncertain significance and one as benign. Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV003517298	SCV004360406	uncertain significance	Malignant hyperthermia, susceptibility to, 5	2023-01-13	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 256 of the CACNA1S protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CACNA1S-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.