Submissions for variant NM_000069.3(CACNA1S):c.1583G>T (p.Arg528Leu)

gnomAD frequency: 0.00001  dbSNP: rs80338777

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549801	SCV000653644	likely pathogenic	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5	2023-03-29	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg528 amino acid residue in CACNA1S. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7847370, 7987325, 9066893, 11034874, 11808349, 15726306, 19822448). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt CACNA1S protein function. ClinVar contains an entry for this variant (Variation ID: 473965). This missense change has been observed in individual(s) with clinical features of autosomal dominant CACNA1S-related conditions (PMID: 29193480; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 528 of the CACNA1S protein (p.Arg528Leu).
GeneDx	RCV002293456	SCV002586928	likely pathogenic	not provided	2024-10-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19118277, 31321302, 29193480, 39333966)
Fulgent Genetics, Fulgent Genetics	RCV002491092	SCV002810880	likely pathogenic	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5; Thyrotoxic periodic paralysis, susceptibility to, 1	2021-09-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003419987	SCV004114546	likely pathogenic	CACNA1S-related disorder	2023-04-13	criteria provided, single submitter	clinical testing	The CACNA1S c.1583G>T variant is predicted to result in the amino acid substitution p.Arg528Leu. This variant has been reported in at least six families with CACNA1S-related disease (Anandan et al. 2018. PubMed ID: 29193480; Table e-1 - Nicolau et al. 2019. PubMed ID: 31321302). Additionally, multiple missense variants impacting this amino acid (p.Arg528His, p.Arg528Cys, p.Arg528Gly) have been reported as pathogenic (Katsuno et al. 2001. PubMed ID: 11808349; Yang et al. 2014. PubMed ID: 25430699; Wang et al. 2005. PubMed ID: 15726306). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-201047043-C-A) and has been interpreted as likely pathogenic by multiple labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/473965/). This variant is interpreted as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003517221	SCV004360382	uncertain significance	Malignant hyperthermia, susceptibility to, 5	2023-02-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 528 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 autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotypes (ClinVar Variation ID: 473965; PMID: 25430699, 29193480, 31321302). This variant has been identified in 3/251124 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.