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NM_000069.3(CACNA1S):c.1493G>A (p.Arg498His)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(4)

Review status:
criteria provided, conflicting interpretations
Submissions:
5 (Most recent: Aug 19, 2021)
Last evaluated:
May 17, 2021
Accession:
VCV000424926.15
Variation ID:
424926
Description:
single nucleotide variant
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NM_000069.3(CACNA1S):c.1493G>A (p.Arg498His)

Allele ID
413260
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
1q32.1
Genomic location
1: 201078005 (GRCh38) GRCh38 UCSC
1: 201047133 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000001.10:g.201047133C>T
NC_000001.11:g.201078005C>T
NG_009816.1:g.39562G>A
... more HGVS
Protein change
R498H
Other names
-
Canonical SPDI
NC_000001.11:201078004:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
0.00060 (A)

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00018
Links
ClinGen: CA078266
dbSNP: rs150590855
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 1 criteria provided, single submitter Oct 28, 2020 RCV000697677.4
Uncertain significance 1 criteria provided, single submitter Apr 27, 2017 RCV001096477.1
Conflicting interpretations of pathogenicity 3 criteria provided, conflicting interpretations May 17, 2021 RCV000487733.6
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
CACNA1S No evidence available No evidence available GRCh38
GRCh37
1137 1152

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Oct 28, 2020)
criteria provided, single submitter
Method: clinical testing
Hypokalemic periodic paralysis 1
Malignant hyperthermia, susceptibility to, 5
Allele origin: germline
Invitae
Accession: SCV000826302.4
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (2)
Comment:
This sequence change replaces arginine with histidine at codon 498 of the CACNA1S protein (p.Arg498His). The arginine residue is highly conserved and there is a … (more)
Uncertain significance
(Oct 01, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV000574805.12
Submitted: (Jul 04, 2021)
Evidence details
Uncertain significance
(Apr 27, 2017)
criteria provided, single submitter
Method: clinical testing
Hypokalemic periodic paralysis 1
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV001252693.1
Submitted: (Feb 20, 2020)
Evidence details
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
Likely benign
(Dec 02, 2019)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: unknown
Athena Diagnostics Inc
Accession: SCV001474977.1
Submitted: (Dec 30, 2020)
Evidence details
Publications
PubMed (2)
Uncertain significance
(May 17, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV001794674.1
Submitted: (Aug 19, 2021)
Evidence details
Comment:
Reported in an individual with exertional heat illness who harbored an additional variant in the CACNA1S gene and was not susceptible to malignant hyperthermia by … (more)

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation. Kobayashi Y Genome medicine 2017 PMID: 28166811
Next-generation Sequencing of RYR1 and CACNA1S in Malignant Hyperthermia and Exertional Heat Illness. Fiszer D Anesthesiology 2015 PMID: 25658027
Using exome data to identify malignant hyperthermia susceptibility mutations. Gonsalves SG Anesthesiology 2013 PMID: 24195946

Text-mined citations for rs150590855...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 07, 2021