1-201077916-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong

The NM_000069.3(CACNA1S):c.1582C>T(p.Arg528Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,942 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R528L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:7O:1

Conservation

PhyloP100: 3.38

Publications

32 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: Pathogenic. The variant received 14 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-201077915-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 473965.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

PP5

Variant 1-201077916-G-A is Pathogenic according to our data. Variant chr1-201077916-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 849085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1S	NM_000069.3 link	c.1582C>T	p.Arg528Cys	missense_variant	Exon 11 of 44	ENST00000362061.4	NP_000060.2
CACNA1S	XM_005245478.4 link	c.1582C>T	p.Arg528Cys	missense_variant	Exon 11 of 43		XP_005245535.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 link	c.1582C>T	p.Arg528Cys	missense_variant	Exon 11 of 44	1	NM_000069.3	ENSP00000355192.3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251160

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461722

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1111878

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

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:

152220

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000267

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Feb 09, 2021

Athena Diagnostics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene (PMID: 33088529, 25430699). Other variants resulting in a different missense change at this codon have been reported to be pathogenic, suggesting this arginine residue is critical and its disruption is likely to be disease-causing (PMID: 7847370, 7987325, 11034874, 11808349). Computational tools yielded predictions that this amino acid change may be damaging to the protein. Clinical presentation is noted to be variable and reduced penetrance has been reported for females (PMID: 28972032, 15726306, 18835861, 20301512).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

Feb 23, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as heterozygous in individuals in the published literature with hypokalemic periodic paralysis, and also in two asymptomatic individuals (PMID: 25430699, 33088529); 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; This variant is associated with the following publications: (PMID: 33088529, 25430699, 37432431)

Hypokalemic periodic paralysis, type 1

Pathogenic:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypokalemic periodic paralysis

Pathogenic:1

Mar 20, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg528Cys variant in CACNA1S has been reported in one individual with hypokalemic periodic paralysis, and segregated with disease in 3 affected male relatives. Two female relatives who carried the variant were asymptomatic (Yang 2014). Of note, incomplete penetrance of hypokalemic periodic paralysis in female individuals has been previously described (Ke 2013). The p.Arg528Cys variant has been identified in 2/111426 of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80338778). Computational prediction tools and conservation analysis suggest that the p.Arg528Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In addition, a different pathogenic variant at this position (p.Arg528His) has been reported in ClinVar (Variation ID: 17625). In summary, although additional studies are required to fully establish its clinical significance, the p.Arg528Cys variant is likely pathogenic. ACMG/AMP criteria applied: PM2, PM5, PP1, PP3.

Congenital myopathy 18

Pathogenic:1

Jun 02, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense c.1582C>T (p.Arg528Cys) variant in the CACNA1S gene has been observed in individual(s) with hypokalaemic periodic paralysis (Yang, Bo et al.,2014). It has also been observed to segregate with disease in related individuals. Other variant(s) that disrupt this residue have been determined to be pathogenic (Katsuno, M et al., 2001). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant is reported with the allele frequency (0.0007%) in the gnomAD Exomes. It is submitted to ClinVar as Likely Pathogenic. The amino acid Arginine at position 528 is changed to a Cystine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid Arginine in CACNA1S is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Functional studies are required to prove the pathoegenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic.

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

Pathogenic:1

Jan 09, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine with cysteine at codon 528 of the CACNA1S protein (p.Arg528Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs80338778, ExAC 0.003%). This variant has been observed in individual(s) with hypokalaemic periodic paralysis (PMID: 25430699). It has also been observed to segregate with disease in related individuals. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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, 11034874, 11808349). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

Malignant hyperthermia, susceptibility to, 5

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.0

.;H

PhyloP100

3.4

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-7.5

D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.93

ClinPred

1.0

GERP RS

4.7

Varity_R

0.89

gMVP

0.90

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over