Submissions for variant NM_000719.7(CACNA1C):c.6272A>G (p.Asn2091Ser)

gnomAD frequency: 0.00074  dbSNP: rs201090446

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001084051	SCV000254657	likely benign	Long QT syndrome	2024-01-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000357942	SCV000329185	uncertain significance	not provided	2023-10-11	criteria provided, single submitter	clinical testing	Reported in association with arrhythmias and sudden unexplained death (Bagnall et al., 2014; Sutphin et al., 2016; Marschall et al., 2019), though also reported as a polymorphism (Wemhner et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a gain of function effect (Sutphin et al., 2016); This variant is associated with the following publications: (PMID: 25633834, 24690944, 27218670, 34426522, 30172029, 24440382, 31737537, 30027834)
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000519629	SCV000616620	uncertain significance	Timothy syndrome	2017-04-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000617693	SCV000737727	uncertain significance	Cardiovascular phenotype	2017-10-20	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient evidence
Ambry Genetics	RCV000717339	SCV000848189	uncertain significance	History of neurodevelopmental disorder	2018-11-08	criteria provided, single submitter	clinical testing	The p.N2091S variant (also known as c.6272A>G), located in coding exon 47 of the CACNA1C gene, results from an A to G substitution at nucleotide position 6272. The asparagine at codon 2091 is replaced by serine, an amino acid with highly similar properties. This variant was detected in a 20-year old sudden death victim with myocyte hypertrophy, and was also detected in a 24-year old female with history of syncope who did not meet Timothy syndrome diagnostic criteria (Bagnall RD et al. Heart Rhythm. 2014;11(4):655-62​; Sutphin BS et al. Congenit Heart Dis, 2016;11(6):683-692). The variant was also detected in a 5-year old male with autism spectrum disorder (ASD), however, he also had 9p21.1 chromosomal deletion affecting the LINGO2 gene which has been associated with ASD (Brett M et al. PLoS ONE, 2014 Apr;9:e93409). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
CeGaT Center for Human Genetics Tuebingen	RCV000357942	SCV001148544	benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	CACNA1C: BP4, BS1, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000357942	SCV002047841	uncertain significance	not provided	2021-01-15	criteria provided, single submitter	clinical testing	The CACNA1C c.6272A>G; p.Asn2091Ser variant (rs201090446) is reported in the literature in an individual with sudden unexpected death and a history of syncope (Sutphin 2016). This variant is found in the general population with an overall allele frequency of 0.05% (129/263770 alleles) in the Genome Aggregation Database. The asparagine at codon 2091 is moderately conserved, and computational analyses predict that this variant is neutral (REVEL: 0.139). However, functional studies of the variant protein indicate altered electrophysiological properties, including increased current density compared to wildtype protein (Sutphin 2016). Due to limited information, the clinical significance of the p.Asn2091Ser variant is uncertain at this time. References: Sutphin et al. Molecular and Functional Characterization of Rare CACNA1C Variants in Sudden Unexplained Death in the Young. Congenit Heart Dis. 2016 Dec;11(6):683-692.
Revvity Omics, Revvity	RCV000357942	SCV003830325	uncertain significance	not provided	2024-01-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003955212	SCV004774382	likely benign	CACNA1C-related disorder	2021-10-28	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV001842950	SCV000804961	uncertain significance	Cardiac arrhythmia	2016-08-18	no assertion criteria provided	clinical testing