Submissions for variant NM_001127222.2(CACNA1A):c.2026G>A (p.Gly676Arg)

dbSNP: rs2144980758

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001758187	SCV001985725	uncertain significance	not provided	2022-11-30	criteria provided, single submitter	clinical testing	Observed in an individual with cerebellar ataxia and reported as likely pathogenic by the authors (Coutelier et al., 2017); 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: 33349592, 28444220, 31115040)
Genetic Services Laboratory, University of Chicago	RCV001758187	SCV002064443	likely pathogenic	not provided	2020-03-11	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CACNA1A gene demonstrated a sequence change, c.2029G>A, in exon 16 that results in an amino acid change, p.Gly677Arg. The p.Gly677Arg change affects a highly conserved amino acid residue located in a pore loop region of domain II of the CACNA1A protein that is known to be functional. The p.Gly677Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This change has been reported in one patient with ataxia (described as c.2026G>A:p.Gly676Arg in the article) (PMID: 28444220). Additionally, a different sequence change affecting the same amino acid residue (p.Gly677Glu) has been described in a patient with episodic ataxia, vertigo, dysarthria and diplopia (PMID: 29062094). This sequence change is absent from the population databases (ExAC and gnomAD). These collective evidences indicate that this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001882838	SCV002146228	pathogenic	Episodic ataxia type 2; Developmental and epileptic encephalopathy, 42	2023-09-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 677 of the CACNA1A protein (p.Gly677Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cerebellar ataxia and/or episodic ataxia (PMID: 28444220, 31115040). It has also been observed to segregate with disease in related individuals. This variant is also known as c.2026G>A (p.G676R). ClinVar contains an entry for this variant (Variation ID: 1303894). 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. This variant disrupts the p.Gly677 amino acid residue in CACNA1A. Other variant(s) that disrupt this residue have been observed in individuals with CACNA1A-related conditions (PMID: 29062094), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV001758187	SCV002770640	pathogenic	not provided	2021-10-08	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been confirmed to occur de novo in one individual with clinical features associated with this gene and appears to segregate with disease in at least one family. Computational tools yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Computational tools predict that this variant is damaging.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004555884	SCV005045044	likely pathogenic	Episodic ataxia type 2	2023-12-26	criteria provided, single submitter	clinical testing	The CACNA1A c.2026G>A (p.Gly676Arg) variant, also known as c.2029G>A (p.Gly677Arg) on NM_023035.3, has been reported in an individual with episodic ataxia and also segregated with disease in a family affected with episodic ataxia and cognitive impairment (Coutelier M et al., PMID: 28444220; Humbertclaude V et al., PMID: 31115040). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by two submitters and a variant of uncertain significance by two submitters. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant is predicted to occur in an alpha helix in the pore loop domain, changes a non-polar glycine to a positively charged arginine, and computational predictors indicate that the variant is damaging, evidence that correlates with impact to CACNA1A function. Additionally, another variant in the same codon, c.2027G>A (p.Gly676Glu), has been described in an individual affected with episodic ataxia (Choi KD et al., PMID: 29062094). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.