NM_000069.3(CACNA1S):c.1583G>A (p.Arg528His) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 31, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000627794.9

Allele description [Variation Report for NM_000069.3(CACNA1S):c.1583G>A (p.Arg528His)]

NM_000069.3(CACNA1S):c.1583G>A (p.Arg528His)

Gene:

CACNA1S:calcium voltage-gated channel subunit alpha1 S [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q32.1

Genomic location:

Preferred name:

NM_000069.3(CACNA1S):c.1583G>A (p.Arg528His)

HGVS:

NC_000001.11:g.201077915C>T
NG_009816.2:g.39652G>A
NM_000069.3:c.1583G>AMANE SELECT
NP_000060.2:p.Arg528His
NC_000001.10:g.201047043C>T
NG_009816.1:g.39652G>A
NM_000069.2:c.1583G>A
Q13698:p.Arg528His

Protein change:

R528H; ARG528HIS

Links:

UniProtKB: Q13698#VAR_001499; OMIM: 114208.0003; dbSNP: rs80338777

NCBI 1000 Genomes Browser:

rs80338777

Molecular consequence:

NM_000069.3:c.1583G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypokalemic periodic paralysis, type 1
Synonyms:: HypoPP
Identifiers:: MONDO: MONDO:0042979; MedGen: C3714580; Orphanet: 681; OMIM: 170400

Name:: Malignant hyperthermia, susceptibility to, 5 (MHS5)
Synonyms:: Malignant hyperthermia susceptibility type 5; Malignant hyperpyrexia susceptibility type 5
Identifiers:: MONDO: MONDO:0011163; MedGen: C1866077; Orphanet: 423; OMIM: 601887

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000653632	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 7847370, 7987325, 9066893, 11034874, 11808349, 15726306, 8605978, 9512357, 9852570, 23187123, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000653632

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 31, 2024)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Hypokalemic periodic paralysis and the dihydropyridine receptor (CACNL1A3): genotype/phenotype correlations for two predominant mutations and evidence for the absence of a founder effect in 16 caucasian families.

Elbaz A, Vale-Santos J, Jurkat-Rott K, Lapie P, Ophoff RA, Bady B, Links TP, Piussan C, Vila A, Monnier N, et al.

Am J Hum Genet. 1995 Feb;56(2):374-80.

PubMed [citation]

PMID:: 7847370
PMCID:: PMC1801148

A calcium channel mutation causing hypokalemic periodic paralysis.

Jurkat-Rott K, Lehmann-Horn F, Elbaz A, Heine R, Gregg RG, Hogan K, Powers PA, Lapie P, Vale-Santos JE, Weissenbach J, et al.

Hum Mol Genet. 1994 Aug;3(8):1415-9.

PubMed [citation]

PMID:: 7987325

See all PubMed Citations (11)

Details of each submission

From Invitae, SCV000653632.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 12, 2024

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