Submissions for variant NM_000719.7(CACNA1C):c.2573G>A (p.Arg858His)

dbSNP: rs786205753

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001509415	SCV000223346	pathogenic	not provided	2022-07-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published in vitro functional studies showed that p.(R858H) results in a gain-of-function of the cardiac L-type calcium channel (PMID: 24728418); This variant is associated with the following publications: (PMID: 29016939, 23174487, 25184293, 24728418, 26707467, 30027834, 30345660, 23631430, 29046645, 30513141, 31395126, 31729605, 32161207, 34691145, 31408100, 32062134, 30530868)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550877	SCV000627524	pathogenic	Long QT syndrome	2025-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 858 of the CACNA1C protein (p.Arg858His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT syndrome (PMID: 23174487, 23631430, 24728418, 29016939, 30345660). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 190653). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1C protein function. Experimental studies have shown that this missense change affects CACNA1C function (PMID: 24728418). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001509415	SCV001472236	likely pathogenic	not provided	2019-09-25	criteria provided, single submitter	clinical testing	The CACNA1C c.2573G>A; p.Arg858His variant (rs786205753) is reported in the literature in multiple individuals with long QT syndrome or episodes of syncope, arrhythmia, or sudden unexpected death (Fukuyama 2014, Gardner 2019, Hellenthal 2017, Mullally 2013). This variant has been observed to co-segregate with disease in several families, including a large five-generation kindred, although it has been noted in asymptomatic relatives, suggesting incomplete penetrance (Fukuyama 2014, Gardner 2019). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 858 is highly conserved, computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious, and functional analyses indicate an increased current density relative to wildtype protein (Fukuyama 2014). Based on available information, this variant is considered to be likely pathogenic. References: Fukuyama M et al. Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes. Europace. 2014 Dec;16(12):1828-37. Gardner RJM et al. Penetrance and expressivity of the R858H CACNA1C variant in a five-generation pedigree segregating an arrhythmogenic channelopathy. Mol Genet Genomic Med. 2019 Jan;7(1):e00476. Hellenthal N et al. Molecular autopsy of sudden unexplained deaths reveals genetic predispositions for cardiac diseases among young forensic cases. Europace. 2017 Nov 1;19(11):1881-1890. Mullally J et al. Risk of life-threatening cardiac events among patients with long QT syndrome and multiple mutations. Heart Rhythm. 2013 Mar;10(3):378-82.
Mayo Clinic Laboratories, Mayo Clinic	RCV001509415	SCV001716112	pathogenic	not provided	2021-01-26	criteria provided, single submitter	clinical testing	PS3, PP1_Strong, PS4_Moderate, PM1, PM2_Supporting, PP2, PP3
Ambry Genetics	RCV002453577	SCV002738922	likely pathogenic	Cardiovascular phenotype	2021-03-05	criteria provided, single submitter	clinical testing	The p.R858H variant (also known as c.2573G>A), located in coding exon 19 of the CACNA1C gene, results from a G to A substitution at nucleotide position 2573. The arginine at codon 858 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in multiple individuals who met clinical criteria for long QT syndrome (LQTS), or had features of LQTS such as QTc prolongation or syncope; some of these individuals were related (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Mullally J et al. Heart Rhythm, 2013 Mar;10:378-82; Fukuyama M et al. Europace, 2014 Dec;16:1828-37; Hellenthal N et al. Europace, 2017 Nov;19:1881-1890; Gardner RJM et al. Mol Genet Genomic Med, 2019 01;7:e00476; Fukuyama M et al. Circ J, 2020 03;84:559-568). This variant was also detected in multiple sudden death cases, one of which had cardiac findings (Hellenthal N et al. Europace, 2017 Nov;19:1881-1890; Larsen MK et al. Int J Legal Med, 2020 Jan;134:111-121). In vitro functional studies suggest that this alteration may impact protein function; however, the clinical significance of these studies is undetermined (Fukuyama M et al. Europace, 2014 Dec;16:1828-37). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 long QT syndrome (LQTS); however, its clinical significance for Timothy syndrome is unclear.
OMIM	RCV000782180	SCV000920648	pathogenic	Long qt syndrome 8	2019-06-05	no assertion criteria provided	literature only
Clinical Genetics, Academic Medical Center	RCV001509415	SCV001917483	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001509415	SCV001957662	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001509415	SCV001978219	pathogenic	not provided		no assertion criteria provided	clinical testing