Submissions for variant NM_001127222.2(CACNA1A):c.835C>T (p.Arg279Cys)

dbSNP: rs1555773764

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000991686	SCV001143349	pathogenic	not provided	2024-02-27	criteria provided, single submitter	clinical testing	This variant has been identified in multiple unrelated individuals with episodic ataxia. Variable presentation and reduced penetrance has also reported. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001035721	SCV001199055	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2022-06-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1A protein function. ClinVar contains an entry for this variant (Variation ID: 545691). This missense change has been observed in individuals with CACNA1A-related conditions (PMID: 26912519, 27066515, 28444220, 30142438). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 279 of the CACNA1A protein (p.Arg279Cys).
GeneDx	RCV000991686	SCV001817277	pathogenic	not provided	2024-09-11	criteria provided, single submitter	clinical testing	Identified in multiple patients with episodic ataxia in published literature (PMID: 27066515, 26912519, 28444220); 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; This variant is associated with the following publications: (PMID: 23344743, 30142438, 27066515, 28444220, 26912519, 31654490, 32899500, 34263451, 35395208, 34102571, 35401678, 37555011, 35722745, 34806130, 38689878)
Wendy Chung Laboratory, Columbia University Medical Center	RCV002227194	SCV002506548	likely pathogenic	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 52	2022-03-20	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV003230272	SCV003928013	likely pathogenic	Developmental and epileptic encephalopathy, 42	2023-06-01	criteria provided, single submitter	clinical testing
Pediatric Department, Xiangya Hospital, Central South University	RCV003230272	SCV003930354	pathogenic	Developmental and epileptic encephalopathy, 42	2021-01-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004025995	SCV004915157	pathogenic	Inborn genetic diseases	2023-10-06	criteria provided, single submitter	clinical testing	The c.835C>T (p.R279C) alteration is located in exon 6 (coding exon 6) of the CACNA1A gene. This alteration results from a C to T substitution at nucleotide position 835, causing the arginine (R) at amino acid position 279 to be replaced by a cysteine (C)._x000D_ _x000D_ ; however, it is unlikely to be causative of CACN1A-related spinocerebellar ataxia. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in one individual and has been reported as heterozygous in three individuals with features consistent with episodic ataxia, type 2 (Tomlinson, 2016; Maksemous, 2016; Angelini, 2019; Waters, 2019; Hommersom, 2022). Additionally, this variant has been reported in multiple individuals with features consistent with CACNA1A-related early onset ataxia (Angelini, 2019; Ghorbani, 2022; Lipman, 2022; Kessi, 2023). One study has shown this variant to segregate with both episodic ataxia, type 2 and CACNA1A-related neurologic disorders within the same family with incomplete penetrance (Angelini, 2019). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV000656726	SCV000778839	pathogenic	Episodic ataxia type 2; Gait ataxia; Epileptic encephalopathy	2018-01-10	no assertion criteria provided	clinical testing	The Arg279Cys variant in CACNA1A has been reported in a family with episodic ataxia type 2 by Maksemous et al, 2016. This variant is absent in GnomAD and ExAC database.
O&I group, Department of Genetics, University Medical Center of Groningen	RCV001849186	SCV001960823	pathogenic	Spinocerebellar ataxia type 6	2021-07-22	no assertion criteria provided	research
GenomeConnect - Brain Gene Registry	RCV003233795	SCV003931145	not provided	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1		no assertion provided	phenotyping only	Variant classified as Likely pathogenic and reported on 02-23-2021 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.