Submissions for variant NM_018896.5(CACNA1G):c.5144G>A (p.Arg1715His)

dbSNP: rs755221106

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000207440	SCV000593821	pathogenic	Spinocerebellar ataxia type 42	2016-06-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763013	SCV000893458	pathogenic	Spinocerebellar ataxia type 42; Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits	2018-10-31	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001267950	SCV001446472	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	RCV000207440	SCV001519114	pathogenic	Spinocerebellar ataxia type 42	2021-01-04	criteria provided, single submitter	research
Genetics and Molecular Pathology, SA Pathology	RCV000207440	SCV002556746	pathogenic	Spinocerebellar ataxia type 42	2021-08-05	criteria provided, single submitter	clinical testing	The CACNA1G c. 5144G>A variant is classified as a PATHOGENIC variant (PS4, PS3, PP1_Strong, PP3, PP5) The variant is a single nucleotide change from a guanine to an adenine at position 5144 which is predicted to change the Arginine at position 1715 in the protein to Histidine. The variant is in exon 29 and is located in protein domains: ion transport domain, and Polycystin cation channel, of the CACNA1G gene. This variant is a recurrent pathogenic variant in the CACNA1G gene, and it has been previously reported in many individuals with Cerebellar ataxias in heterozygoys state (PMID: 26456284, 26715324, 28490766, 29629410) (PS4). This variant is in dbSNP (rs755221106) but is absent from population databases. In vitro functonal studies have demonstrated that this variant had resulted in a significant shift of the steady-state activation curve towards more positive membrane potential values, whereas the inactivation curve had a higher slope factor, supporting the damaging effect on the gene or gene product (PMID: 26456284, 26715324) (PS3). Multiple pedigrees of Cerebellar ataxia-affected families with this variant has been previously reported showing segregation of this variant with the disorder (PMID: PMID: 26456284, 26715324, 28490766, 29629410) (PP1_Strong). The variant has been reported in the ClinVar (Variation ID: 221981) and HGMD (Accession: CM1511857) as Pathogenic (PP5). Computational predictions support a deleterious effect on the gene or gene product (PP3).
GeneDx	RCV001267950	SCV002599867	pathogenic	not provided	2022-05-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on membrane potential dependency (Coutelier et al., 2015; Morino et al., 2015); 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: 29915382, 34426522, 30200108, 29474447, 35054808, 29421541, 31892274, 30842224, 32878331, 32638069, 34248568, 31999455, 34220096, 33746731, 31229688, 33243296, 31836334, 28490766, 26715324, 33624863, 31692161, 26456284, 29629410, 33163565, 31217264)
OMIM	RCV000207440	SCV000262713	pathogenic	Spinocerebellar ataxia type 42	2018-08-14	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000509294	SCV000607251	not provided	CACNA1G-related disorder		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.