Submissions for variant NM_000069.3(CACNA1S):c.4747G>A (p.Glu1583Lys)

gnomAD frequency: 0.00026  dbSNP: rs148273582

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000364529	SCV000352945	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Invitae	RCV000651260	SCV000773111	likely benign	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5	2024-01-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235183	SCV003934007	likely benign	not specified	2023-05-16	criteria provided, single submitter	clinical testing	Variant summary: CACNA1S c.4747G>A (p.Glu1583Lys) results in a conservative amino acid change located in the Voltage-dependent calcium channel, alpha-1 subunit, IQ domain (IPR014873) 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 0.00027 in 251234 control chromosomes (gnomAD). The observed variant frequency is approximately 220 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 benign. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV003326400	SCV004032995	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	CACNA1S: BS2
Genome-Nilou Lab	RCV003456056	SCV004181068	likely benign	Malignant hyperthermia, susceptibility to, 5	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003454874	SCV004181069	likely benign	Thyrotoxic periodic paralysis, susceptibility to, 1	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003458397	SCV004181070	likely benign	Congenital myopathy 18	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000364529	SCV004181071	likely benign	Hypokalemic periodic paralysis, type 1	2023-04-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003456056	SCV004360329	likely benign	Malignant hyperthermia, susceptibility to, 5	2022-11-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003940100	SCV004754329	likely benign	CACNA1S-related condition	2020-02-14	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).