Submissions for variant NM_001127222.2(CACNA1A):c.4988G>A (p.Arg1663Gln)

dbSNP: rs121908247

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000406556	SCV000329829	pathogenic	not provided	2023-08-14	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect by significantly impairing the function of the protein (PMID: 28742085); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28742085, 16325861, 24486772, 32429945, 32637629, 37555011, 33349592, 34068417)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415457	SCV000492918	likely pathogenic	Global developmental delay; Enlarged cisterna magna	2014-05-20	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000406556	SCV000612550	likely pathogenic	not provided	2017-06-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000653331	SCV000775210	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects CACNA1A function (PMID: 28742085). 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: 68432). This missense change has been observed in individual(s) with early onset ataxia (PMID: 16325861, 28742085). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1664 of the CACNA1A protein (p.Arg1664Gln).
Ambry Genetics	RCV002311540	SCV000846881	likely pathogenic	Inborn genetic diseases	2019-04-16	criteria provided, single submitter	clinical testing	The p.R1664Q variant (also known as c.4991G>A), located in coding exon 32 of the CACNA1A gene, results from a G to A substitution at nucleotide position 4991. The arginine at codon 1664 is replaced by glutamine, an amino acid with highly similar properties. The variant disrupts the R2 position of the voltage sensing motif in the voltage sensing domain which is known to be crucial for proper gating (Bezanilla F. Nat. Rev. Mol. Cell Biol., 2008 Apr;9:323-32; Chamberlin A et al. J. Mol. Biol., 2015 Jan;427:131-45). In one study, this alteration was identified as a de novo occurrence in four individuals with severe early onset ataxia, global developmental delay, hypotonia, and ophthalmologic abnormalities. In addition, two studies performed in drosophilla showed that this alteration acts as a loss of function mutation and only partially rescues lethality (Oriel C et al. Int J Mol Sci, 2018 Jul;19:; Luo X et al. PLoS Genet., 2017 Jul;13:e1006905). In another study, this variant was identified to be de novo with early onset, non-fluctuating limb and trunk ataxia (Tonelli A et al. J. Neurol. Sci., 2006 Feb;241:13-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV002273953	SCV002559122	pathogenic	Neurodevelopmental delay		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000406556	SCV003813096	pathogenic	not provided	2023-09-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003152591	SCV003841211	pathogenic	Developmental and epileptic encephalopathy, 42		criteria provided, single submitter	clinical testing
3billion	RCV000059302	SCV003841799	pathogenic	Spinocerebellar ataxia type 6	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068432). The variant has been previously reported as de novo in at least two similarly affected unrelated individuals (PMID: 28742085). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16325861, 28742085). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Pediatric Department, Xiangya Hospital, Central South University	RCV003152591	SCV003930353	pathogenic	Developmental and epileptic encephalopathy, 42	2021-01-07	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV003152591	SCV005418671	pathogenic	Developmental and epileptic encephalopathy, 42		criteria provided, single submitter	clinical testing	PM2_Supporting+PS4_Moderate+PS2_VeryStrong+PP4+PS3_Moderate
UniProtKB/Swiss-Prot	RCV000059302	SCV000090860	not provided	Spinocerebellar ataxia type 6		no assertion provided	not provided
Mendelics	RCV000157057	SCV000199322	pathogenic	Chronic and progressive ataxia	2014-11-30	no assertion criteria provided	clinical testing
Baylor Genetics	RCV000679889	SCV000807290	uncertain significance	Episodic ataxia type 2	2017-09-01	flagged submission	clinical testing	This mutation has been previously reported as disease-causing and was found four times in our laboratory as de novo findings in affected individuals.
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	RCV000755049	SCV000882749	pathogenic	Ataxia _ Neurologic (child onset); Non-progressive congenital cerebellar ataxia	2019-02-11	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000406556	SCV001963387	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000406556	SCV001968847	likely pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV000406556	SCV002760025	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 12-08-2021 by Lab or GTR ID 500031. 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. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.
Solve-RD Consortium	RCV003152591	SCV005091512	likely pathogenic	Developmental and epileptic encephalopathy, 42	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team