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NM_000719.7(CACNA1C):c.1553G>A (p.Arg518His) AND Hypertrophic cardiomyopathy 1

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Apr 19, 2017
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:
RCV000584800.2

Allele description [Variation Report for NM_000719.7(CACNA1C):c.1553G>A (p.Arg518His)]

NM_000719.7(CACNA1C):c.1553G>A (p.Arg518His)

Gene:
CACNA1C:calcium voltage-gated channel subunit alpha1 C [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
12p13.33
Genomic location:
Preferred name:
NM_000719.7(CACNA1C):c.1553G>A (p.Arg518His)
HGVS:
  • NC_000012.12:g.2566466G>A
  • NG_008801.2:g.600681G>A
  • NM_000719.7:c.1553G>AMANE SELECT
  • NM_001129827.2:c.1553G>A
  • NM_001129829.2:c.1553G>A
  • NM_001129830.3:c.1553G>A
  • NM_001129831.2:c.1553G>A
  • NM_001129832.2:c.1553G>A
  • NM_001129833.2:c.1553G>A
  • NM_001129834.2:c.1553G>A
  • NM_001129835.2:c.1553G>A
  • NM_001129836.2:c.1553G>A
  • NM_001129837.2:c.1553G>A
  • NM_001129838.2:c.1553G>A
  • NM_001129839.2:c.1553G>A
  • NM_001129840.2:c.1553G>A
  • NM_001129841.2:c.1553G>A
  • NM_001129842.2:c.1553G>A
  • NM_001129843.2:c.1553G>A
  • NM_001129844.2:c.1544G>A
  • NM_001129846.2:c.1553G>A
  • NM_001167623.2:c.1553G>A
  • NM_001167624.3:c.1553G>A
  • NM_001167625.2:c.1553G>A
  • NM_199460.4:c.1553G>A
  • NP_000710.5:p.Arg518His
  • NP_001123299.1:p.Arg518His
  • NP_001123301.1:p.Arg518His
  • NP_001123302.2:p.Arg518His
  • NP_001123303.1:p.Arg518His
  • NP_001123304.1:p.Arg518His
  • NP_001123305.1:p.Arg518His
  • NP_001123306.1:p.Arg518His
  • NP_001123307.1:p.Arg518His
  • NP_001123308.1:p.Arg518His
  • NP_001123309.1:p.Arg518His
  • NP_001123310.1:p.Arg518His
  • NP_001123311.1:p.Arg518His
  • NP_001123312.1:p.Arg518His
  • NP_001123313.1:p.Arg518His
  • NP_001123314.1:p.Arg518His
  • NP_001123315.1:p.Arg518His
  • NP_001123316.1:p.Arg515His
  • NP_001123318.1:p.Arg518His
  • NP_001161095.1:p.Arg518His
  • NP_001161096.2:p.Arg518His
  • NP_001161097.1:p.Arg518His
  • NP_955630.3:p.Arg518His
  • LRG_334t1:c.1553G>A
  • LRG_334t2:c.1553G>A
  • LRG_334:g.600681G>A
  • NC_000012.11:g.2675632G>A
  • NM_000719.6:c.1553G>A
  • NM_001129827.1:c.1553G>A
  • NM_001167624.2:c.1553G>A
Protein change:
R515H; ARG518HIS
Links:
OMIM: 114205.0017; dbSNP: rs1057517711
NCBI 1000 Genomes Browser:
rs1057517711
Molecular consequence:
  • NM_000719.7:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129827.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129829.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129830.3:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129831.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129832.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129833.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129834.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129835.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129836.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129837.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129838.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129839.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129840.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129841.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129842.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129843.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129844.2:c.1544G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001129846.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167623.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167624.3:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167625.2:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_199460.4:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hypertrophic cardiomyopathy 1
Synonyms:
Familial hypertrophic cardiomyopathy 1; MYH7-Related Familial Hypertrophic Cardiomyopathy
Identifiers:
MONDO: MONDO:0008647; MedGen: C3495498; OMIM: 192600

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000692528Agnes Ginges Centre for Molecular Cardiology, Centenary Institute
criteria provided, single submitter

(Agnes Ginges Centre for Molecular Cardiology criteria (2015))		Likely pathogenic
(Apr 19, 2017) 		germlineresearch

PubMed (1)
[See all records that cite this PMID]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedresearch

Citations

PubMed

Identification and Functional Characterization of a Novel CACNA1C-Mediated Cardiac Disorder Characterized by Prolonged QT Intervals With Hypertrophic Cardiomyopathy, Congenital Heart Defects, and Sudden Cardiac Death.

Boczek NJ, Ye D, Jin F, Tester DJ, Huseby A, Bos JM, Johnson AJ, Kanter R, Ackerman MJ.

Circ Arrhythm Electrophysiol. 2015 Oct;8(5):1122-32. doi: 10.1161/CIRCEP.115.002745. Epub 2015 Aug 7.

PubMed [citation]
PMID:
26253506
PMCID:
PMC5094060

Details of each submission

From Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, SCV000692528.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)

Description

The CACNA1C Arg518His variant had been identified in a few probands with mixed phenotypes of Long QT, congenital heart defects and HCM (Boczek NJ, et al., 2015; Genedx, personal communication) and has been found to segregate in 2 families with varying phenotypes (Boczek NJ, et al., 2015). In vitro functional analysis using whole cell patch clamping confirmed the loss of current density and inactivation in combination with increased window and later voltage gated calcium channel current (Boczek NJ, et al., 2015), however this study may not necessarily reflect biological function and future studies will be useful to validate these findings. The variant is present a singleton event in the Exome Aggregation Consortium dataset (MAF= 0.00003230, http://exac.broadinstitute.org/). We identified this variant in a patient diagnosed with HCM in their adoloscence, the patient had a known family history of disease and a prolonged QT was noted when the patient was in his 40s. The probands affected son also harbours this variant. He was diagnosed with HCM at 2 months. Computational tools SIFT, PolyPhen-2 and MutationTaster predict this variant to have deleterious effect. In summary, based on a few proband's reported with similar phenotypes, strong segregation data, rarity in general population databases, as well supportive in silico tools in combination with a functional study suggestive of an affect on protein function, we classify the CACNA1C Arg518His as "likely pathogenic".

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024