chr1-201077915-C-T

Position:

chr1-201077915-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000069.3(CACNA1S):c.1583G>A(p.Arg528His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R528G) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13O:1

Conservation

PhyloP100: 7.87

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a transmembrane_region Helical; Name=S4 of repeat II (size 18) in uniprot entity CAC1S_HUMAN there are 8 pathogenic changes around while only 2 benign (80%) in NM_000069.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-201077916-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 849085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.956

PP5

Variant 1-201077915-C-T is Pathogenic according to our data. Variant chr1-201077915-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201077915-C-T is described in Lovd as [Pathogenic]. Variant chr1-201077915-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3 linkuse as main transcript	c.1583G>A	p.Arg528His	missense_variant	11/44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 linkuse as main transcript	c.1583G>A	p.Arg528His	missense_variant	11/43		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 linkuse as main transcript	c.1583G>A	p.Arg528His	missense_variant	11/44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypokalemic periodic paralysis, type 1

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	This variant was identified as compound heterozygous. -
Pathogenic, no assertion criteria provided	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 22, 2017	The observed variant c.1583G>A (p.Arg528His) is not reported in 1000 Genomes and ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, damaging by SIFT, and probably damaging by PolyPhen2. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Aug 01, 2019	This variant has been previously reported as a heterozygous change in patients in multiple affected familities with hypokalemic periodic paralysis, characterized by muscle weakness (PMID: 7987325, 7847370, 11034874, 15098604) and other diverse phenotypes, including muscle atrophy and myopathy (PMID: 17587224, 28972032). Incomplete penetrance in female family members has been reported for this variant (PMID: 7847370, 15098604). Functional studies have demonstrated that this variant alters the electrophysiological properties of the calcium channel, including potassium-dependent paradoxical membrane depolarization (PMID: 8605978, 9512357, 19225109), and a mouse model of this variant recapitulates the essential features of hypokalemic periodic paralysis in humans, including muscle weakness (PMID: 23187123). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1583G>A (p.Arg528His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant, a change from a strongly positive arginine residue to a weakly positive histidine residue, occurs within the S4 transmembrane segment of the channel pore, which appears to participate in voltage sensing. Based on the available evidence, the c.1583G>A (p.Arg528His) variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	Apr 12, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1999	- -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 11, 2023	The frequency of this variant in the general population is consistent with pathogenicity. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) This variant segregates with HOKPP in multiple families, including several with observed incomplete penetrance. This variant has been confirmed to occur de novo in multiple individuals with clinical features of HOKPP associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant has been shown to disrupt CACNA1S calcium channel function, causing potassium-dependent paradoxical membrane depolarization in response to hypokalemia (PMID: 8605978, 19225109, 23187123). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2022	Reported previously in affected individuals from several families with hypokalemic periodic paralysis (Elbaz et al., 1995); Published functional studies demonstrate that this variant results in a significantly reduced whole cell calcium channel current and depolarization of the resting cell potential in response to hypokalemia (Lapie et al., 1996; Wu et al., 2012); 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: 20541469, 22253645, 17587224, 11328898, 28325641, 28857175, 28972032, 31567646, 31447099, 33584831, 7847370, 9512357, 23187123, 19225109, 11034874, 7987325, 19825159, 25983995, 31068157, 31380823, 19118277, 8605978, 11591859, 11808349, 15098604, 9066893, 7650604, 25088161, 32528171) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 02, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	CACNA1S: PS4, PM2, PM5, PS3:Moderate, PP1, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 30, 2020	PS3, PS4_moderate, PM6, PM2, PP3 -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 14, 2024

- -

CACNA1S-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 25, 2024

The CACNA1S c.1583G>A variant is predicted to result in the amino acid substitution p.Arg528His. This variant has been frequently reported in patients with hypokalemic periodic paralysis (Jurkat-Rott et al. 1994. PubMed ID: 7987325; Jurkat-Rott et al. 2009. PubMed ID: 19225109; Luo et al. 2019. PubMed ID: 31068157). A mouse model of the p.Arg528His variant displays many of the human clinical features of hypokalemic periodic paralysis (Wu et al. 2012. PubMed ID: 23187123). This variant has not been reported in gnomAD, indicating this variant is rare. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 528 of the CACNA1S protein (p.Arg528His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypokalemic periodic paralysis (PMID: 7847370, 7987325, 9066893, 11034874, 11808349, 15726306). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17625). 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: 8605978, 9512357, 9852570, 23187123). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.3

.;H

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-4.7

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.97

MutPred

0.82

Loss of MoRF binding (P = 0.0268);Loss of MoRF binding (P = 0.0268);

MVP

0.96

MPC

0.59

ClinPred

1.0

GERP RS

4.7

Varity_R

0.93

gMVP

0.87

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over