ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.2573G>A (p.Arg858His) (rs786205753)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000550877 SCV000627524 pathogenic Long QT syndrome 2020-09-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 858 of the CACNA1C protein (p.Arg858His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (rs786205753, ExAC no frequency). This variant has been observed to segregate with long QT syndrome in families (PMID: 24728418, 29016939, 30345660), and has been reported in individuals affected with this disease or referred for long QT syndrome genetic testing (PMID: 24728418, 23174487, 23631430). ClinVar contains an entry for this variant (Variation ID: 190653). This variant has been reported to affect CACNA1C protein function (PMID: 24728418). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285756 SCV001472236 likely pathogenic none 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
OMIM RCV000782180 SCV000920648 pathogenic Long QT syndrome 8 2019-06-05 no assertion criteria provided literature only

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