Submissions for variant NM_001127222.2(CACNA1A):c.4043G>A (p.Arg1348Gln)

dbSNP: rs1057520918

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000435974	SCV000520000	pathogenic	not provided	2021-10-27	criteria provided, single submitter	clinical testing	Published functional studies in the Tg5J mouse model, which harbors an equivalent variant, demonstrated a shift in both voltage activation and inactivation to lower voltage, suggesting that the Arg1349 residue is critical for sensing Ca(v)2.1 voltage changes (Miki et al., 2008; Knierim et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26814174, 28007337, 25596066, 21183743, 18597946, 23831250, 20097664, 28717674, 19811514, 30063100, 31139143, 32860008, 31785789)
Athena Diagnostics Inc	RCV000435974	SCV000612538	pathogenic	not provided	2014-07-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624902	SCV000741128	pathogenic	Inborn genetic diseases	2015-10-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763033	SCV000893508	pathogenic	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1; Developmental and epileptic encephalopathy, 42	2018-10-31	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000787277	SCV001132540	pathogenic	Developmental and epileptic encephalopathy, 42	2018-11-15	criteria provided, single submitter	research	The heterozygous p.Arg1348Gln variant in CACNA1A was identified by our study in one individual with Early Infantile Epileptic Encephalopaty. The p.Arg1348Gln variant is pathogenic based off of multiple reports in ClinVar and the literature.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001078138	SCV001167344	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2020-02-20	criteria provided, single submitter	clinical testing	A heterozygous missense variant c.4043G>A in exon 25 of the CACNA1A gene that results in the amino acid substitution of Glutamine for Arginine at codon 1348 was detected. The observed variant has not been reported in the 1000 Genomes and ExAC databases. The observed variant lies in the Ion transport protein domain of the CACNA1A protein and has previously been reported (as Arg1350Gln) in patients affected with congenital cerebellar ataxia (Bahamonde et al.2015) and is a current de novo variant reported in multiple unrelated individuals affected with ataxia and developmental delay (ClinVar). The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
Centogene AG - the Rare Disease Company	RCV001251039	SCV001426438	pathogenic	Spinocerebellar ataxia type 6		criteria provided, single submitter	clinical testing
Invitae	RCV001078138	SCV001589925	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1349 of the CACNA1A protein (p.Arg1349Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CACNA1A-related conditions (PMID: 20097664, 21183743, 23831250, 26814174, 28007337, 31139143). In at least one individual the variant was observed to be de novo. This variant is also known as p.Arg1350Gln, p.R1352Q. ClinVar contains an entry for this variant (Variation ID: 380972). 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. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000787277	SCV001950113	pathogenic	Developmental and epileptic encephalopathy, 42	2021-07-19	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed).
Genetic Services Laboratory, University of Chicago	RCV000435974	SCV002064439	pathogenic	not provided	2018-01-09	criteria provided, single submitter	clinical testing
Wendy Chung Laboratory, Columbia University Medical Center	RCV002227161	SCV002506531	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
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000787277	SCV002818455	likely pathogenic	Developmental and epileptic encephalopathy, 42		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000435974	SCV003813074	pathogenic	not provided	2022-07-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000787277	SCV003835478	pathogenic	Developmental and epileptic encephalopathy, 42	2022-09-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000435974	SCV004011031	pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	CACNA1A: PS2:Very Strong, PM2, PP2, PP3
Baylor Genetics	RCV003333066	SCV004041384	pathogenic	Episodic ataxia type 2	2023-04-19	criteria provided, single submitter	clinical testing
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	RCV000787277	SCV000926208	pathogenic	Developmental and epileptic encephalopathy, 42	2019-05-03	no assertion criteria provided	clinical testing
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV000787277	SCV001482311	pathogenic	Developmental and epileptic encephalopathy, 42		no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV003223404	SCV002548532	not provided	Episodic ataxia type 2; Spinocerebellar ataxia type 6; Migraine, familial hemiplegic, 1		no assertion provided	phenotyping only	Variant reported in multiple GenomeConnect participants by multiple clinical testing laboratories. Variant interpreted as Pathogenic by all laboratories and reported most recently on 07-19-2018 by lab GeneDx and on 08-06-2018 by lab Greenwood Genetics Laboratories. 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 John Constantino MD PhD 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.
Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	RCV000787277	SCV004167601	pathogenic	Developmental and epileptic encephalopathy, 42	2022-09-21	no assertion criteria provided	clinical testing