Submissions for variant NM_001127222.2(CACNA1A):c.4979G>A (p.Arg1660His)

dbSNP: rs121908216

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000517293	SCV000612549	likely pathogenic	not provided	2022-04-14	criteria provided, single submitter	clinical testing	This variant segregates with episodic ataxia in one family (PMID: 10987655) and is also reported in an unrelated individual with pure cerebellar ataxia (PMID: 29482223). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as Arg1666His or Arg1660His. Computational tools predict that this variant is damaging.
GeneDx	RCV000517293	SCV000617514	pathogenic	not provided	2023-09-10	criteria provided, single submitter	clinical testing	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: 16325861, 11179022, 11814735, 26814174, 28742085, 34507393, 29482223, 34758253, 10987655, 35401678, 34806130)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000009017	SCV000886432	likely pathogenic	Episodic ataxia type 2	2018-10-23	criteria provided, single submitter	research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000517293	SCV001480076	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
Invitae	RCV001381850	SCV001580407	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1661 of the CACNA1A protein (p.Arg1661His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of, or diagnosis of, episodic ataxia (PMID: 10987655, 29482223). It has also been observed to segregate with disease in related individuals. This variant is also known as Arg1666His. ClinVar contains an entry for this variant (Variation ID: 8495). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Genomics England Pilot Project, Genomics England	RCV001542800	SCV001760436	likely pathogenic	Spinocerebellar ataxia type 6		criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000517293	SCV002064442	likely pathogenic	not provided	2021-02-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CACNA1A gene demonstrated a sequence change, c.4982G>A, in exon 32 that results in an amino acid change, p.Arg1661His. This sequence change has not been described in the gnomAD general population database. This sequence change has been described in a family with episodic ataxia type 2 and familial hemiplegic migraine, and was shown to co-segregate with the disease phenotype (PMID: 10987655). The p.Arg1661His change affects a highly conserved amino acid residue located in the S4 transmembrane segment of domain IV of the CACNA1A protein. It appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Collectively these evidences suggests this p.Arg1661His variant is likely pathogenic, however functional studies have not been performed to prove this conclusively.
CeGaT Center for Human Genetics Tuebingen	RCV000517293	SCV002498433	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	CACNA1A: PP1:Strong, PM1, PM2, PS4:Moderate, PP2
OMIM	RCV000009017	SCV000029232	pathogenic	Episodic ataxia type 2	1999-09-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000009017	SCV000090859	not provided	Episodic ataxia type 2		no assertion provided	not provided
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000517293	SCV001929906	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000517293	SCV001958634	likely pathogenic	not provided		no assertion criteria provided	clinical testing
O&I group, Department of Genetics, University Medical Center of Groningen	RCV001542800	SCV001960826	likely pathogenic	Spinocerebellar ataxia type 6	2021-07-22	no assertion criteria provided	research
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000517293	SCV001977702	pathogenic	not provided		no assertion criteria provided	clinical testing