ClinVar Miner

Submissions for variant NM_000069.3(CACNA1S):c.4060A>T (p.Thr1354Ser) (rs145910245)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586717 SCV000233318 likely benign not provided 2021-09-16 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 32222817, 29193480, 29212769, 27153395, 27181684, 28011884, 20861472, 24784157, 24055113, 25735680, 25637381, 24195946, 26332594, 27147545)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000181043 SCV000538556 uncertain significance not specified 2016-04-25 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.4% (252/66740) Europeans. Classified as VUS in 3 papers (7 total papers in HGMD)
Invitae RCV001081599 SCV000653710 likely benign Hypokalemic periodic paralysis 1; Malignant hyperthermia, susceptibility to, 5 2020-11-27 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586717 SCV000695297 uncertain significance not provided 2016-10-19 criteria provided, single submitter clinical testing Variant summary: The CACNA1S c.4060A>T (p.Thr1354Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 287/121696 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0037758 (252/66740). This frequency is about 604 times the estimated maximal expected allele frequency of a pathogenic CACNA1S variant (0.0000063), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant was initially considered pathogenic based on a publication showing segregation of the variant in an affected family, absence in 268 control chromosomes, and functional data demonstrating abnormal Ca++ flux (Pirone_2010). Based on this evidence, Lawrence_2013 listed the variant of interest as a reportable incidental finding in exome sequencing cases. However, the high frequency of this variant in the general population puts into question the true pathogenicity of the variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as a VUS until additional evidence becomes available.
Athena Diagnostics Inc RCV000586717 SCV001143496 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000586717 SCV001147594 uncertain significance not provided 2021-06-01 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148444 SCV000190143 uncertain significance Malignant hyperthermia, susceptibility to, 1 2014-06-01 no assertion criteria provided research

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