Submissions for variant NM_000069.3(CACNA1S):c.4025C>T (p.Ser1342Leu)

gnomAD frequency: 0.00001  dbSNP: rs563795648

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001347104	SCV001541349	uncertain significance	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5	2023-02-21	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with CACNA1S-related conditions. ClinVar contains an entry for this variant (Variation ID: 1043053). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CACNA1S protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1342 of the CACNA1S protein (p.Ser1342Leu). This variant is present in population databases (rs563795648, gnomAD 0.003%).
GeneDx	RCV001776209	SCV002013588	uncertain significance	not provided	2019-11-06	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV005005194	SCV002793028	uncertain significance	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5; Thyrotoxic periodic paralysis, susceptibility to, 1; Congenital myopathy 18	2023-12-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449972	SCV004181193	uncertain significance	Malignant hyperthermia, susceptibility to, 5	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449973	SCV004181194	uncertain significance	Thyrotoxic periodic paralysis, susceptibility to, 1	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003458674	SCV004181195	uncertain significance	Congenital myopathy 18	2023-04-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV003449971	SCV004181196	uncertain significance	Hypokalemic periodic paralysis, type 1	2023-04-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003449972	SCV004839990	uncertain significance	Malignant hyperthermia, susceptibility to, 5	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 1342 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 not been identified 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.