1-201091993-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PP3_StrongBS1_Supporting

The NM_000069.3(CACNA1S):c.520C>T(p.Arg174Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,614,012 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Synonymous variant affecting the same amino acid position (i.e. R174R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

drug response reviewed by expert panel P:15U:1O:7

Conservation

PhyloP100: 5.32

Publications

38 publications found

Variant links:

Genes affected

CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

CACNA1S Gene-Disease associations (from GenCC):

congenital myopathy 18
Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
hypokalemic periodic paralysis, type 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
malignant hyperthermia, susceptibility to, 5
Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
congenital myopathy
Inheritance: SD, AR, AD Classification: STRONG Submitted by: Illumina, Genomics England PanelApp
hypokalemic periodic paralysis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CACNA1S links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000185 (27/1461866) while in subpopulation EAS AF = 0.000504 (20/39700). AF 95% confidence interval is 0.000333. There are 0 homozygotes in GnomAdExome4. There are 13 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000069.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	NM_000069.3	MANE Select	c.520C>T	p.Arg174Trp	missense	Exon 4 of 44	NP_000060.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.520C>T	p.Arg174Trp	missense	Exon 4 of 44	ENSP00000355192.3
CACNA1S	ENST00000367338.7	TSL:5	c.520C>T	p.Arg174Trp	missense	Exon 4 of 43	ENSP00000356307.3
CACNA1S	ENST00000681874.1		c.520C>T	p.Arg174Trp	missense	Exon 4 of 43	ENSP00000505162.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251362

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111996

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000386

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.608

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000389

Hom.:

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: drug response

Submissions summary: Pathogenic:15Uncertain:1Other:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 5

Pathogenic:8

Aug 31, 2025

Clinical Genomics Laboratory, Washington University in St. Louis

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CACNA1S c.520C>T (p.Arg174Trp) variant has been reported in several individuals affected with malignant hyperthermia with positive in vitro contracture or caffeine halothane contracture testing and is reported to segregate with disease in at least one family (Carpenter D et al., PMID: 19825159; Klingler W et al., PMID: 24433488; Levano S et al., PMID: 28259615; Miller DM et al., PMID: 30236257). This variant has been reported in the ClinVar database as a germline pathogenic variant by an expert panel. This variant is only observed in 30/1,614,012 alleles in the general population (gnomAD v.4.1.0), indicating it is not a common variant. Computational predictors indicate that the variant is damaging, evidence that correlates with impact to CACNA1S function. In support of this prediction, functional studies show this variant causes the channel to be impaired (Bannister RA and Beam KG, PMID: 23663834; Eltit JM et al., PMID: 22547813). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic.

Mar 27, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Apr 11, 2023

New York Genome Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.520C>T variant in CACNA1S has previously been reported in individuals with malignant hyperthermia susceptibility [PMID: 19825159, 24433488, 30236257], and it has been deposited in ClinVar as Pathogenic by an expert panel (PharmGKB Expert Review Panel [ClinVar ID: 575733]). The c.520C>T variant is observed in 11 alleles (0.0018% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.520C>T variant is located in exon 4 of this 44-exon gene and is predicted to replace an evolutionarily conserved arginine amino acid with tryptophan at position 174 (p.(Arg174Trp)) in the S4 helix of the first conserved membrane repeat of the encodedprotein that is known to be important in sensing changes in the membrane potential [PMID: 19825159, 23663834]. In vitro studies demonstrated elevated resting myoplasmic calcium levels and partially depleted sarcoplasmic reticulum stores in myoblast cells carrying the c.520C>T variant [PMID: 23663834, 22547813]. Basedon available evidence this heterozygous c.520C>T p.(Arg174Trp) variant identified in CACNA1S is classified as Pathogenic.

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.

Nov 09, 2020

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 10, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces arginine with tryptophan at codon 174 of the CACNA1S protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. A functional study in vitro has shown that this variant increases sensitivity to isoflurane and halothane compared to wild-type protein (PMID: 22547813). In a knock-in mouse model, this variant did not appear to be insufficient to trigger a fulminant response to halothane or confer heat stress intolerance (PMID: 37392848). This variant has been reported in at least six individuals affected with malignant hyperthermia susceptibility (PMID: 19825159, 24433488, 28259615, 30236257, 33564012, 33564012, DOI: 10.24811/hjms.71.1-2_31). In one family, this variant was observed in a proband and his mother affected with malignant hyperthermia susceptibility and was absent in his unaffected sibling (PMID: 19825159). This variant has been identified in 7/251362 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.520C>T (p.Arg174Trp) variant, located on the exon 4 of the CACNA1S gene, replaces glycine with tryptophan at codon 174 of the CACNA1S protein. This missense change has been observed in at least six unrelated individuals with personal or family histories of a malignant hyperthermia susceptibility (MHS), positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) (PMID: 19825159, 24433488, 28259615, 30236257, 33564012, https://doi.org/10.24811/hjms.71.1-2_31). This variant has been observed to segregate with MHS in one family member (PMID: 19825159). Functional studies demonstrate impaired calcium ion depolarization and increased sensitivity of calcium ion release to caffeine and volatile anesthetics (PMID: 23663834, 22547813). Computational prediction (REVEL score 0.91) suggests that this variant may have deleterious impact on protein structure and function. ClinVar contains an entry for this variant (ID: 575733). This variant is rare (30/1614012 chromosomes) in the general population database (gnomAD). For these reasons, the c.520C>T (p.Arg174Trp) variant in the CACNA1S gene is classified as likely pathogenic.

Jan 31, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PS4,PS3_SUP,PM2_SUP,PP1,PP3

not provided

Pathogenic:3

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1S: PS4:Moderate, PM2:Supporting, PP3, PP4, PS3:Supporting

Jun 17, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 10, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate impaired Ca2+ depolarization and increased sensitivity of Ca2+ release to caffeine and volatile anesthetics, while R174W-expressing myotubes had elevated Ca2+ levels and sarcoplasmic reticulum stores were partially depleted (PMID: 22547813, 23663834); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27147545, 23663834, 21664226, 21845430, 24433488, 34426522, 30236257, 30476936, 37728764, 38127101, 19825159, 22547813, 19118277)

Inborn genetic diseases

Pathogenic:1

Aug 08, 2025

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.520C>T (p.R174W) alteration is located in exon 4 (coding exon 4) of the CACNA1S gene. This alteration results from a C to T substitution at nucleotide position 520, causing the arginine (R) at amino acid position 174 to be replaced by a tryptophan (W). Based on data from gnomAD, the c.520C>T allele has an overall frequency of 0.0028% (7/251362) total alleles studied. The highest observed frequency was 0.01087% (2/18394) of East Asian alleles. This variant was reported in individual(s) with features consistent with CACNA1S-related malignant hyperthermia susceptibility (Carpenter, 2009; Klingler, 2014; Kanzaki, 2022). The p.R174 amino acid is conserved in available vertebrate species. In multiple assays testing CACNA1S function, this variant showed functionally abnormal and functionally normal results (Eltit, 2012; Bannister, 2013; Savalli, 2021; Feng, 2023). The p.R174W alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.

Malignant hyperthermia of anesthesia

Pathogenic:1

Jun 01, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory

Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1

Pathogenic:1

Mar 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 174 of the CACNA1S protein (p.Arg174Trp). This variant is present in population databases (rs772226819, gnomAD 0.01%). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia susceptibility (PMID: 1982519, 24433488, 30236257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 575733). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CACNA1S function (PMID: 22547813, 23663834). 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.

not specified

Pathogenic:1

Mar 30, 2023

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Malignant hyperthermia, susceptibility to, 5;C2749982:Thyrotoxic periodic paralysis, susceptibility to, 1;C3714580:Hypokalemic periodic paralysis, type 1;C5830283:Congenital myopathy 18

Uncertain:1

Feb 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

methoxyflurane response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method: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. Drug-variant association: Toxicity

enflurane response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

halothane response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

desflurane response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

succinylcholine response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

sevoflurane response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

isoflurane response - Toxicity

Other:1

Mar 24, 2021

PharmGKB

Significance:drug response

Review Status:reviewed by expert panel

Collection Method:curation

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

5.2

PhyloP100

5.3

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-7.0

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MVP

0.98

MPC

0.54

ClinPred

1.0

GERP RS

4.5

Varity_R

0.81

gMVP

0.91

Mutation Taster

=8/92

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over