GeneBe

rs772226819

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP3_StrongPP5_Strong

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

16
2
1

Clinical Significance

drug response reviewed by expert panel P:12O:7

Conservation

PhyloP100: 5.32
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.951
PP5
Variant 1-201091993-G-A is Pathogenic according to our data. Variant chr1-201091993-G-A is described in ClinVar as [drug_response]. Clinvar id is 575733.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=6, Likely_pathogenic=6, drug_response=7}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CACNA1SNM_000069.3 linkuse as main transcriptc.520C>T p.Arg174Trp missense_variant 4/44 ENST00000362061.4 NP_000060.2 Q13698
CACNA1SXM_005245478.4 linkuse as main transcriptc.520C>T p.Arg174Trp missense_variant 4/43 XP_005245535.1 B1ALM3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CACNA1SENST00000362061.4 linkuse as main transcriptc.520C>T p.Arg174Trp missense_variant 4/441 NM_000069.3 ENSP00000355192.3 Q13698

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152146
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251362
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135858
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 SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000185
AC:
27
AN:
1461866
Hom.:
0
Cov.:
33
AF XY:
0.0000179
AC XY:
13
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000324
Hom.:
0
Bravo
AF:
0.00000756
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: drug response
Submissions summary: Pathogenic:12Other:7
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 5 Pathogenic:6
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 31, 2024Criteria applied: PS4,PS3_SUP,PM2_SUP,PP1,PP3 -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenNov 09, 2020- -
Likely pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthSep 27, 2024The 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. -
Pathogenic, criteria provided, single submitterclinical testingNew York Genome CenterApr 11, 2023The 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. -
Likely pathogenic, criteria provided, single submitterclinical testingJuno Genomics, Hangzhou Juno Genomics, Inc-PM2_Supporting+PS3+PS4_Supporting+PP1 -
Likely pathogenic, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthSep 01, 2023This 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 (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study in myotubes showed that this variant increases sensitivity to isoflurane and halothane compared to wild-type protein (PMID: 22547813). 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. -
not provided Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenJun 17, 2021- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 26, 2024Published 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: 23663834, 21664226, 21845430, 24433488, 34426522, 30236257, 30476936, 37728764, 38127101, 19825159, 22547813, 19118277) -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2021- -
not specified Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMendelicsMar 30, 2023- -
Malignant hyperthermia of anesthesia Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 01, 2023proposed classification - variant undergoing re-assessment, contact laboratory -
Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 02, 2024This 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. -
methoxyflurane response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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
sevoflurane response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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
isoflurane response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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
halothane response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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
desflurane response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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
succinylcholine response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.85
D;D
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
5.2
.;H
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-7.0
D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
.;D
Vest4
0.93
MVP
0.98
MPC
0.54
ClinPred
1.0
D
GERP RS
4.5
Varity_R
0.81
gMVP
0.91

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs772226819; hg19: chr1-201061121; COSMIC: COSV62941213; API