Submissions for variant NM_000069.3(CACNA1S):c.3257G>A (p.Arg1086His)

dbSNP: rs1800559

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PharmGKB	RCV001787808	SCV002031213	drug response	enflurane response - Toxicity	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB	RCV001787809	SCV002031220	drug response	halothane response - Toxicity	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB	RCV001787810	SCV002031222	drug response	isoflurane response - Toxicity	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB	RCV001787811	SCV002031232	drug response	methoxyflurane response - Toxicity	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB	RCV001787812	SCV002031241	drug response	sevoflurane response - Toxicity	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB	RCV001787813	SCV002031242	drug response	succinylcholine response - Toxicity	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
PharmGKB	RCV003227606	SCV003925481	drug response	desflurane response - Toxicity	2021-03-24	reviewed by expert panel	curation	PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance.
GeneDx	RCV001753422	SCV002007115	pathogenic	not provided	2024-09-04	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect; specifically, R1086H enhances RyR1 sensitivity to activation by both endogenous (voltage sensor) and exogenous (caffeine) activators (PMID: 15201141); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.3333G>A due to alternative nomenclature; This variant is associated with the following publications: (PMID: 20431982, 19825159, 11260227, 31851124, 34256322, 27147545, 34608571, 9199552, 15201141)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851936	SCV002138384	pathogenic	Hypokalemic periodic paralysis, type 1; Malignant hyperthermia, susceptibility to, 5	2022-01-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CACNA1S function (PMID: 20213496). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 17626). This missense change has been observed in individual(s) with malignant hyperthermia susceptibility (PMID: 9199552, 11260227, 16163667). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs1800559, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1086 of the CACNA1S protein (p.Arg1086His).
Color Diagnostics, LLC DBA Color Health	RCV000019193	SCV004360351	pathogenic	Malignant hyperthermia, susceptibility to, 5	2023-08-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1086 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). A functional study has shown that this variant results in the increased sensitivity to RYR1 agonist (caffeine) (PMID: 15201141). This variant has been reported in multiple individuals affected with malignant hyperthermia susceptibility (PMID: 9199552, 11260227, 12411788). This variant has been shown to segregate with disease in three unrelated families (over ten informative meiosis; PMID: 9199552, 11260227, 12411788). This variant has been identified in 1/251440 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000019193	SCV004830347	pathogenic	Malignant hyperthermia, susceptibility to, 5	2023-06-20	criteria provided, single submitter	clinical testing	Functional studies suggest that this variant results in a deleterious effect on the protein (PMID: 15201141). This variant has been reported in multiple individuals with malignant hyperthermia susceptibility (PMID: 26188342, 31851124, 28011884, 9199552, 11260227, 12411788, 20431982). This variant is present in 1/251440 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). A different missense substitution at this amino acid residue has been previously reported in individual(s) with disease and classified as likely pathogenic, which supports the functional importance of this position. This variant has been reported to co-segregate with disease in affected individuals in one family (PMID: 9199552). This variant is predicted to be deleterious by in silico analysis.
OMIM	RCV000019193	SCV000039481	risk factor	Malignant hyperthermia, susceptibility to, 5	2001-03-01	no assertion criteria provided	literature only