NM_000069.3(CACNA1S):c.1582C>T (p.Arg528Cys) AND multiple conditions

Clinical significance:Likely pathogenic (Last evaluated: Jan 9, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001052970.1

Allele description [Variation Report for NM_000069.3(CACNA1S):c.1582C>T (p.Arg528Cys)]

NM_000069.3(CACNA1S):c.1582C>T (p.Arg528Cys)

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.1582C>T (p.Arg528Cys)
HGVS:
  • NC_000001.11:g.201077916G>A
  • NG_009816.1:g.39651C>T
  • NG_009816.2:g.39651C>T
  • NM_000069.3:c.1582C>TMANE SELECT
  • NP_000060.2:p.Arg528Cys
  • NC_000001.10:g.201047044G>A
  • NM_000069.2:c.1582C>T
Protein change:
R528C
Molecular consequence:
  • NM_000069.3:c.1582C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hypokalemic periodic paralysis 1 (HOKPP1)
Synonyms:
HypoPP
Identifiers:
MONDO: MONDO:0042979; MedGen: C3714580; Orphanet: 681; OMIM: 170400
Name:
Malignant hyperthermia, susceptibility to, 5
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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001217210Invitaecriteria provided, single submitter
Likely pathogenic
(Jan 9, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Clinical-molecular study of a family with essential tremor, late onset seizures and periodic paralysis.

Domínguez-Morán JA, Barón M, de Blas G, Orensanz LM, Jiménez-Escrig A.

Seizure. 2000 Oct;9(7):493-7.

PubMed [citation]
PMID:
11034874

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 (6)

Details of each submission

From Invitae, SCV001217210.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 7, 2021

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