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NM_000069.3(CACNA1S):c.4060A>T (p.Thr1354Ser)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(2);Uncertain significance(4)

Review status:
criteria provided, conflicting interpretations
Submissions:
7 (Most recent: Sep 24, 2021)
Last evaluated:
Sep 16, 2021
Accession:
VCV000161208.14
Variation ID:
161208
Description:
single nucleotide variant
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NM_000069.3(CACNA1S):c.4060A>T (p.Thr1354Ser)

Allele ID
171056
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
1q32.1
Genomic location
1: 201051037 (GRCh38) GRCh38 UCSC
1: 201020165 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000001.10:g.201020165T>A
NC_000001.11:g.201051037T>A
NG_009816.1:g.66530A>T
... more HGVS
Protein change
T1354S
Other names
-
Canonical SPDI
NC_000001.11:201051036:T:A
Functional consequence
-
Global minor allele frequency (GMAF)
0.00080 (A)

Allele frequency
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00369
1000 Genomes Project 0.00080
Trans-Omics for Precision Medicine (TOPMed) 0.00317
The Genome Aggregation Database (gnomAD) 0.00271
The Genome Aggregation Database (gnomAD) 0.00349
Links
ClinGen: CA004058
dbSNP: rs145910245
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 Apr 25, 2016 RCV000181043.6
Likely benign 1 criteria provided, single submitter Nov 27, 2020 RCV001081599.2
Conflicting interpretations of pathogenicity 4 criteria provided, conflicting interpretations Sep 16, 2021 RCV000586717.9
Uncertain significance 1 no assertion criteria provided Jun 1, 2014 RCV000148444.2
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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
1139 1154

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely benign
(Sep 16, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000233318.9
Submitted: (Sep 24, 2021)
Evidence details
Comment:
This variant is associated with the following publications: (PMID: 32222817, 29193480, 29212769, 27153395, 27181684, 28011884, 20861472, 24784157, 24055113, 25735680, 25637381, 24195946, 26332594, 27147545)
Uncertain significance
(Apr 25, 2016)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000538556.1
Submitted: (Apr 03, 2017)
Evidence details
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Uncertain significance
(Oct 19, 2016)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695297.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (2)
Comment:
Variant summary: The CACNA1S c.4060A>T (p.Thr1354Ser) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant … (more)
Uncertain significance
(Jan 07, 2019)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Athena Diagnostics Inc
Accession: SCV001143496.1
Submitted: (Sep 25, 2019)
Evidence details
Publications
PubMed (11)
Likely benign
(Nov 27, 2020)
criteria provided, single submitter
Method: clinical testing
Hypokalemic periodic paralysis 1
Malignant hyperthermia, susceptibility to, 5
Allele origin: germline
Invitae
Accession: SCV000653710.5
Submitted: (Jan 07, 2021)
Evidence details
Uncertain significance
(Jun 01, 2021)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV001147594.7
Submitted: (Jul 04, 2021)
Evidence details
Uncertain significance
(Jun 01, 2014)
no assertion criteria provided
Method: research
Malignant hyperthermia
(Autosomal dominant inheritance)
Allele origin: germline
CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190143.1
Submitted: (Aug 28, 2014)
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
Evidence details

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
Functional and structural characterization of a novel malignant hyperthermia-susceptible variant of DHPR-β<sub>1a</sub> subunit (CACNB1). Perez CF American journal of physiology. Cell physiology 2018 PMID: 29212769
Rhabdomyolysis and fluctuating asymptomatic hyperCKemia associated with CACNA1S variant. Anandan C European journal of neurology 2018 PMID: 29193480
Pharmacogenetics and pathophysiology of CACNA1S mutations in malignant hyperthermia. Beam TA Physiological genomics 2017 PMID: 28011884
Comparison of pathogenicity prediction tools on missense variants in RYR1 and CACNA1S associated with malignant hyperthermia. Schiemann AH British journal of anaesthesia 2016 PMID: 27147545
Identification of Medically Actionable Secondary Findings in the 1000 Genomes. Olfson E PloS one 2015 PMID: 26332594
Analysis of the entire ryanodine receptor type 1 and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) coding regions for variants associated with malignant hyperthermia in Australian families. Gillies RL Anaesthesia and intensive care 2015 PMID: 25735680
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Amendola LM Genome research 2015 PMID: 25637381
The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience. Lawrence L Genetics in medicine : official journal of the American College of Medical Genetics 2014 PMID: 24784157
Using exome data to identify malignant hyperthermia susceptibility mutations. Gonsalves SG Anesthesiology 2013 PMID: 24195946
Actionable, pathogenic incidental findings in 1,000 participants' exomes. Dorschner MO American journal of human genetics 2013 PMID: 24055113
Identification and functional characterization of malignant hyperthermia mutation T1354S in the outer pore of the Cavalpha1S-subunit. Pirone A American journal of physiology. Cell physiology 2010 PMID: 20861472

Text-mined citations for rs145910245...

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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 Nov 27, 2021