NM_000069.3(CACNA1S):c.3715C>G (p.Arg1239Gly) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 4, 2021
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:: RCV000693727.7

Allele description [Variation Report for NM_000069.3(CACNA1S):c.3715C>G (p.Arg1239Gly)]

NM_000069.3(CACNA1S):c.3715C>G (p.Arg1239Gly)

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.3715C>G (p.Arg1239Gly)

HGVS:

NC_000001.11:g.201053539G>C
NG_009816.2:g.64028C>G
NM_000069.3:c.3715C>GMANE SELECT
NP_000060.2:p.Arg1239Gly
NC_000001.10:g.201022667G>C
NG_009816.1:g.64028C>G
NM_000069.2:c.3715C>G
Q13698:p.Arg1239Gly

Protein change:

R1239G; ARG1239GLY

Links:

UniProtKB: Q13698#VAR_001501; OMIM: 114208.0002; dbSNP: rs28930069

NCBI 1000 Genomes Browser:

rs28930069

Molecular consequence:

NM_000069.3:c.3715C>G - 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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000821608	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 4, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 7847370, 17418573, 19225109, 8004673, 15716625, 18162704, 18229654, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000821608

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 4, 2021)

germline

clinical testing

PubMed (8)
[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

Hypokalaemic periodic paralysis due to the CACNA1S R1239H mutation in a large African family.

Houinato D, Laleye A, Adjien C, Adjagba M, Sternberg D, Hilbert P, Vallat JM, Darboux RB, Funalot B, Avode DG.

Neuromuscul Disord. 2007 May;17(5):419-22. Epub 2007 Apr 5.

PubMed [citation]

PMID:: 17418573

See all PubMed Citations (8)

Details of each submission

From Invitae, SCV000821608.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1239 amino acid residue in CACNA1S. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7847370, 17418573, 19225109). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 17624). This missense change has been observed in individual(s) with hypokalemic periodic paralysis (PMID: 8004673, 15716625, 18162704, 18229654). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 1239 of the CACNA1S protein (p.Arg1239Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine.

#	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

ClinVar

Relating variation to medicine