ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.1352C>T (p.Ser451Leu)

gnomAD frequency: 0.00005  dbSNP: rs35521793
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000263862 SCV000353135 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.
GeneDx RCV000484498 SCV000572370 uncertain significance not provided 2022-06-28 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV000697995 SCV000826633 likely benign Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5 2023-11-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV003165797 SCV003862751 uncertain significance Inborn genetic diseases 2023-02-27 criteria provided, single submitter clinical testing The c.1352C>T (p.S451L) alteration is located in exon 10 (coding exon 10) of the CACNA1S gene. This alteration results from a C to T substitution at nucleotide position 1352, causing the serine (S) at amino acid position 451 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV003517182 SCV004360394 uncertain significance Malignant hyperthermia, susceptibility to, 5 2022-11-06 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 451 of the CACNA1S protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 12/251448 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.

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