ClinVar Genomic variation as it relates to human health

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)

CACNA1S: BS2

This sequence change is predicted to replace threonine with serine at codon 1354 of the CACNA1S protein (p.(Thr1354Ser)). The threonine residue is conserved to fish species, which also have a serine residue at codon 1354 (100 vertebrates, UCSC). The variant is located in the extracellular portion of an ion transporter domain. There is a small physicochemical difference between threonine and serine. The variant is present in a large population cohort at a frequency of 0.52% in the European (non-Finnish) population (rs1145910245, gnomAD v3.0). This variant has been reported in a multigenerational family of individuals who were malignant hyperthermia susceptible (PMID: 20861472) and in two unrelated individuals in an Australian cohort, one of which also had a variant in RYR1 (PMID: 25735680). Patch-clamp analyses demonstrate accelerated inward Ca2+ current and increased sensitisation of RYR1 under caffeine exposure in a transfection model. Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predicting benign/neutral effect, 2/6 algorithms predicting deleterious effect). Based on the classification guidelines RMH Modified ACMG Guidelines v1.3.0, this variant is classified as BENIGN. The following criteria are met: BA1, PP1_Moderate.

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.

This variant is associated with the following publications: (PMID: 32222817, 29193480, 29212769, 27153395, 27181684, 28011884, 20861472, 24784157, 24055113, 25735680, 25637381, 24195946, 26332594, 27147545)

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).