NM_000069.3(CACNA1S):c.3716G>A (p.Arg1239His) AND Hypokalemic periodic paralysis, type 1

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Apr 11, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000019190.45

Allele description [Variation Report for NM_000069.3(CACNA1S):c.3716G>A (p.Arg1239His)]

NM_000069.3(CACNA1S):c.3716G>A (p.Arg1239His)

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.3716G>A (p.Arg1239His)

Other names:

NM_000069.2(CACNA1S):c.3716G>A(p.Arg1239His)

HGVS:

NC_000001.11:g.201053538C>T
NG_009816.2:g.64029G>A
NM_000069.3:c.3716G>AMANE SELECT
NP_000060.2:p.Arg1239His
NC_000001.10:g.201022666C>T
NG_009816.1:g.64029G>A
NM_000069.2:c.3716G>A
Q13698:p.Arg1239His

Protein change:

R1239H; ARG1239HIS

Links:

UniProtKB: Q13698#VAR_001502; OMIM: 114208.0001; dbSNP: rs28930068

NCBI 1000 Genomes Browser:

rs28930068

Molecular consequence:

NM_000069.3:c.3716G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000039478	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 1995)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 8004673, 3037387, 7847370
SCV000040412	GeneReviews	no classification provided	not provided	germline	literature only
SCV000803550	SIB Swiss Institute of Bioinformatics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 31, 2018)	unknown	curation	PubMed (7) [See all records that cite these PMIDs] 8004673, 18162704, 17418573, 19118277, 28857175, 29572832, 25741868
SCV001976700	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 1, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34008892, 25741868
SCV002012153	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 2, 2021)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 29572832, 28857175, 19225109, 34008892, 26252573, 25741868
SCV002061170	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 34008892, 11555352, 21841462, 25213595, 20301512, 19225109, 29572832, 25741868
SCV002600038	Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	no assertion criteria provided	Pathogenic (Apr 12, 2022)	germline	research
SCV004177654	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 11, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Primary structure of the receptor for calcium channel blockers from skeletal muscle.

Tanabe T, Takeshima H, Mikami A, Flockerzi V, Takahashi H, Kangawa K, Kojima M, Matsuo H, Hirose T, Numa S.

Nature. 1987 Jul 23-29;328(6128):313-8.

PubMed [citation]

PMID:: 3037387

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

See all PubMed Citations (16)

Details of each submission

From OMIM, SCV000039478.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

In patients with hypokalemic periodic paralysis (HOKPP1; 170400), Ptacek et al. (1994) demonstrated a heterozygous G-to-A transition at a position analogous to basepair 3716 in rabbit cDNA (Tanabe et al., 1987). The change from CGT to CAT predicted substitution of an arginine residue by a histidine at a position corresponding to amino acid 1239 in the rabbit DHP receptor. This arginine is completely conserved among genes encoding DHP receptors from rabbit, carp, ray, and human skeletal muscle. Elbaz et al. (1995) demonstrated a de novo heterozygous arg1239-to-his mutation.

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

From GeneReviews, SCV000040412.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	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

From SIB Swiss Institute of Bioinformatics, SCV000803550.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (7)

Description

This variant is interpreted as a Pathogenic, for Periodic paralysis hypokalemic 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:8004673). PS2 => De novo (paternity and maternity confirmed). Only paternity confirmed, but since article has been published in 1994, we can assume no need to confirm maternity (PMID:8004673). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation (PMID:8004673,18162704,17418573,19118277). PS3 => Well-established functional studies show a deleterious effect (PMID:28857175,29572832).

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

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV001976700.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

PM1, PM2, PM5, PP3, PP5

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

From 3billion, SCV002012153.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

Same nucleotide change resulting in same amino acid change has been previously reported as de novo and observed in at least two similarly affected unrelated individuals (PMID:34008892, 26252573, PS2, PS4_M). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:29572832, 28857175, 19225109, PS3). It is not observed in the gnomAD v2.1.1 dataset (PM2). A different missense change at the same codon (p.Arg1239Gly) has been reported as pathogenic (VCV000017624.7, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.971, 3Cnet: 0.869, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From DASA, SCV002061170.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (8)

Description

The c.3716G>A;p.(Arg1239His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17623; OMIM: 114208.0001; PMID: 34008892; 11555352; 21841462; 25213595; 20301512PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 19225109; 29572832) - PS3_moderate. This variant is not present in population databases (rs28930068, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 17624 - c.3715C>G;p.(Arg1239Gly) - ) - PM5. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 34008892) - PM6. The variant co-segregated with disease in multiple affected family members (PMID: 7847370; 17418573; 11555352) - PP1_strong. In summary, the currently available evidence indicates that the variant is pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, SCV002600038.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

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

From Genome-Nilou Lab, SCV004177654.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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