NM_000069.3(CACNA1S):c.2690G>A (p.Arg897Lys) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 19, 2022
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:: RCV000545029.6

Allele description [Variation Report for NM_000069.3(CACNA1S):c.2690G>A (p.Arg897Lys)]

NM_000069.3(CACNA1S):c.2690G>A (p.Arg897Lys)

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.2690G>A (p.Arg897Lys)

HGVS:

NC_000001.11:g.201066284C>T
NG_009816.2:g.51283G>A
NM_000069.3:c.2690G>AMANE SELECT
NP_000060.2:p.Arg897Lys
NC_000001.10:g.201035412C>T
NG_009816.1:g.51283G>A
NM_000069.2:c.2690G>A

Protein change:

R897K

Links:

dbSNP: rs1287079817

NCBI 1000 Genomes Browser:

rs1287079817

Molecular consequence:

NM_000069.3:c.2690G>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
SCV000653678	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 19, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18835861, 22901280, 33005891, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000653678

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 19, 2022)

germline

clinical testing

PubMed (4)
[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

Early onset of hypokalaemic periodic paralysis caused by a novel mutation of the CACNA1S gene.

Chabrier S, Monnier N, Lunardi J.

J Med Genet. 2008 Oct;45(10):686-8. doi: 10.1136/jmg.2008.059766.

PubMed [citation]

PMID:: 18835861

Exploring the utility of whole-exome sequencing as a diagnostic tool in a child with atypical episodic muscle weakness.

Hanchard NA, Murdock DR, Magoulas PL, Bainbridge M, Muzny D, Wu Y, Wang M, Lupski JR, Gibbs RA, Brown CW.

Clin Genet. 2013 May;83(5):457-461. doi: 10.1111/j.1399-0004.2012.01951.x. Epub 2012 Sep 11.

PubMed [citation]

PMID:: 22901280
PMCID:: PMC3926310

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000653678.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg897 amino acid residue in CACNA1S. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18835861, 22901280). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects CACNA1S function (PMID: 33005891). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 473979). This missense change has been observed in individuals with autosomal dominant hypokalemic periodic paralysis (PMID: 33005891). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 897 of the CACNA1S protein (p.Arg897Lys).

#	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: Feb 28, 2024

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