NM_000719.7(CACNA1C):c.2578C>G (p.Arg860Gly) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 17, 2024
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:: RCV004020034.1

Allele description [Variation Report for NM_000719.7(CACNA1C):c.2578C>G (p.Arg860Gly)]

NM_000719.7(CACNA1C):c.2578C>G (p.Arg860Gly)

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.2578C>G (p.Arg860Gly)

Other names:

p.R860G:CGA>GGA

HGVS:

NC_000012.12:g.2593260C>G
NG_008801.2:g.627475C>G
NM_000719.7:c.2578C>GMANE SELECT
NM_001129827.2:c.2578C>G
NM_001129829.2:c.2578C>G
NM_001129830.3:c.2578C>G
NM_001129831.2:c.2578C>G
NM_001129832.2:c.2578C>G
NM_001129833.2:c.2578C>G
NM_001129834.2:c.2578C>G
NM_001129835.2:c.2578C>G
NM_001129836.2:c.2578C>G
NM_001129837.2:c.2578C>G
NM_001129838.2:c.2578C>G
NM_001129839.2:c.2578C>G
NM_001129840.2:c.2578C>G
NM_001129841.2:c.2578C>G
NM_001129842.2:c.2578C>G
NM_001129843.2:c.2578C>G
NM_001129844.2:c.2569C>G
NM_001129846.2:c.2578C>G
NM_001167623.2:c.2578C>G
NM_001167624.3:c.2578C>G
NM_001167625.2:c.2578C>G
NM_199460.4:c.2578C>G
NP_000710.5:p.Arg860Gly
NP_001123299.1:p.Arg860Gly
NP_001123301.1:p.Arg860Gly
NP_001123302.2:p.Arg860Gly
NP_001123303.1:p.Arg860Gly
NP_001123304.1:p.Arg860Gly
NP_001123305.1:p.Arg860Gly
NP_001123306.1:p.Arg860Gly
NP_001123307.1:p.Arg860Gly
NP_001123308.1:p.Arg860Gly
NP_001123309.1:p.Arg860Gly
NP_001123310.1:p.Arg860Gly
NP_001123311.1:p.Arg860Gly
NP_001123312.1:p.Arg860Gly
NP_001123313.1:p.Arg860Gly
NP_001123314.1:p.Arg860Gly
NP_001123315.1:p.Arg860Gly
NP_001123316.1:p.Arg857Gly
NP_001123318.1:p.Arg860Gly
NP_001161095.1:p.Arg860Gly
NP_001161096.2:p.Arg860Gly
NP_001161097.1:p.Arg860Gly
NP_955630.3:p.Arg860Gly
LRG_334t1:c.2578C>G
LRG_334:g.627475C>G
NC_000012.11:g.2702426C>G
NM_000719.6:c.2578C>G

Protein change:

R857G

Links:

dbSNP: rs758786846

NCBI 1000 Genomes Browser:

rs758786846

Molecular consequence:

NM_000719.7:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129827.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129829.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129830.3:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129831.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129832.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129833.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129834.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129835.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129836.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129837.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129838.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129839.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129840.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129841.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129842.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129843.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129844.2:c.2569C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001129846.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167623.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167624.3:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167625.2:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_199460.4:c.2578C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005036687	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25633834, 31408100 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005036687

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Jan 17, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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

Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome.

Wemhöner K, Friedrich C, Stallmeyer B, Coffey AJ, Grace A, Zumhagen S, Seebohm G, Ortiz-Bonnin B, Rinné S, Sachse FB, Schulze-Bahr E, Decher N.

J Mol Cell Cardiol. 2015 Mar;80:186-95. doi: 10.1016/j.yjmcc.2015.01.002. Epub 2015 Jan 26.

PubMed [citation]

PMID:: 25633834

Type 8 long QT syndrome: pathogenic variants in CACNA1C-encoded Cav1.2 cluster in STAC protein binding site.

Mellor GJ, Panwar P, Lee AK, Steinberg C, Hathaway JA, Bartels K, Christian S, Balaji S, Roberts JD, Simpson CS, Boczek NJ, Tester DJ, Radbill AE, Mok NS, Hamilton RM, Kaufman ES, Eugenio PL, Weiss R, January C, McDaniel GM, Leather RA, Erickson C, et al.

Europace. 2019 Nov 1;21(11):1725-1732. doi: 10.1093/europace/euz215.

PubMed [citation]

PMID:: 31408100

Details of each submission

From Ambry Genetics, SCV005036687.1

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

Description

The p.R860G variant (also known as c.2578C>G), located in coding exon 19 of the CACNA1C gene, results from a C to G substitution at nucleotide position 2578. The arginine at codon 860 is replaced by glycine, an amino acid with dissimilar properties. This variant has been detected in probands with prolonged QTc intervals (Wemhöner K et al. J Mol Cell Cardiol, 2015 Mar;80:186-95; Mellor GJ et al. Europace, 2019 Nov;21:1725-1732). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of CACNA1C-related long QT syndrome/Timothy syndrome; however, its clinical significance for CACNA1C-related neurodevelopmental disorder is unclear.

#	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: May 7, 2024

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