Submissions for variant NM_000719.7(CACNA1C):c.2579G>A (p.Arg860Gln)

gnomAD frequency: 0.00001  dbSNP: rs730880056

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001704240	SCV000223347	uncertain significance	not provided	2021-03-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28616568, 29071820, 28600387)
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000853602	SCV000996570	likely pathogenic	Timothy syndrome	2019-03-25	criteria provided, single submitter	clinical testing
Invitae	RCV001057570	SCV001222069	uncertain significance	Long QT syndrome	2021-09-15	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg860 amino acid residue in CACNA1C. Other variant(s) that disrupt this residue have been observed in individuals with CACNA1C-related conditions (PMID: 25633834; Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 190654). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 28600387, 28616568, 29071820, 31408100; Invitae). This variant is present in population databases (rs730880056, ExAC 0.003%). This sequence change replaces arginine with glutamine at codon 860 of the CACNA1C protein (p.Arg860Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.
Ambry Genetics	RCV002453578	SCV002739588	uncertain significance	Cardiovascular phenotype	2020-03-29	criteria provided, single submitter	clinical testing	The p.R860Q variant (also known as c.2579G>A), located in coding exon 19 of the CACNA1C gene, results from a G to A substitution at nucleotide position 2579. The arginine at codon 860 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in long QT syndrome (LQTS) cases; however, in some cases clinical details were limited and/or an additional cardiac variant was also detected (Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10:[Epub ahead of print]; Boles U et al. Int J Cardiol Heart Vasc, 2017 Jun;15:21-23; Seo SH et al. Ann Lab Med, 2018 Jan;38:54-58). Alternate amino acid substitutions at this codon, p.R860G and p.R860P, have also been associated with LQTS (Mellor GJ et al. Europace, 2019 Nov;21:1725-1732). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000656216	SCV000678410	uncertain significance	Wolff-Parkinson-White pattern	2017-07-14	no assertion criteria provided	research	This variant was identified in an individual with Wolff-Parkinson-White syndrome
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001704240	SCV001928328	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001704240	SCV001954522	likely pathogenic	not provided		no assertion criteria provided	clinical testing