Submissions for variant NM_000069.3(CACNA1S):c.1465C>T (p.Arg489Cys)

gnomAD frequency: 0.00013  dbSNP: rs138364213

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000658423	SCV000780195	uncertain significance	not provided	2021-02-12	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Illumina Laboratory Services, Illumina	RCV001096478	SCV001252694	uncertain significance	Hypokalemic periodic paralysis, type 1	2018-01-12	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	RCV001855376	SCV002202684	benign	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5	2023-11-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002536327	SCV003699825	uncertain significance	Inborn genetic diseases	2021-10-29	criteria provided, single submitter	clinical testing	The c.1465C>T (p.R489C) alteration is located in exon 11 (coding exon 11) of the CACNA1S gene. This alteration results from a C to T substitution at nucleotide position 1465, causing the arginine (R) at amino acid position 489 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV003392506	SCV004120688	uncertain significance	CACNA1S-related disorder	2023-03-20	criteria provided, single submitter	clinical testing	The CACNA1S c.1465C>T variant is predicted to result in the amino acid substitution p.Arg489Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-201047161-G-A). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004004191	SCV004817821	uncertain significance	Malignant hyperthermia, susceptibility to, 5	2023-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 489 of the CACNA1S protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 been identified in 19/282876 chromosomes 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.