Submissions for variant NM_018896.5(CACNA1G):c.2881G>A (p.Ala961Thr)

dbSNP: rs886041505

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000263291	SCV000330170	pathogenic	not provided	2022-10-20	criteria provided, single submitter	clinical testing	Published functional studies of the A961T variant demonstrate a gain of function effect by impairing the inactivation of the channel (Chemin et al., 2018); 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: 29878067, 31217264, 33098379, 32736238, 31836334, 31785789, 30842224)
Ambry Genetics	RCV000624028	SCV000742235	pathogenic	Inborn genetic diseases	2024-06-04	criteria provided, single submitter	clinical testing	The c.2881G>A (p.A961T) alteration is located in coding exon 13 of the CACNA1G gene. This alteration results from a G to A substitution at nucleotide position 2881, causing the alanine (A) at amino acid position 961 to be replaced by a threonine (T). The CACNA1G c.2881G>A alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individual(s) with features consistent with CACNA1G-related spinocerebellar ataxia (Chemin, 2018; Martinez-Rubio, 2023). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	RCV000677308	SCV004011725	pathogenic	Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits	2023-07-10	criteria provided, single submitter	clinical testing	The heterozygous variant c.2881G>A (p.Ala961Thr) has been identified in a proband with global developmental delay, sparse hair, decreased tone, speech defects, inability to handle objects, stranger anxiety, axial hypotonia, limb hypotonia, dystonia and increased levels of glutaric acid on GCMS. This variant has not been reported in gnomAD (aggregated) database (PM2_moderate). Computational tools predict a deleterious effect of the mis-sense variant (PP3_moderate). This variant has been reported previously (PP5_supporting). PMID: 29878067. Segregation in the parents confirms that this is a de-novo variant in the proband.
OMIM	RCV000677308	SCV000803433	pathogenic	Spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits	2018-08-14	no assertion criteria provided	literature only
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV001264626	SCV001442905	pathogenic	Neurodevelopmental abnormality	2020-06-04	no assertion criteria provided	clinical testing