Submissions for variant NM_001378452.1(ITPR1):c.106C>T (p.Arg36Cys)

dbSNP: rs2124927471

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002051254	SCV002107579	pathogenic	not provided	2023-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 36 of the ITPR1 protein (p.Arg36Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of spinocerebellar ataxia (PMID: 27572814, 28620721). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1350168). 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 ITPR1 protein function. Experimental studies have shown that this missense change affects ITPR1 function (PMID: 28620721). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002545403	SCV003543215	uncertain significance	Inborn genetic diseases	2022-05-27	criteria provided, single submitter	clinical testing	The c.106C>T (p.R36C) alteration is located in exon 4 (coding exon 2) of the ITPR1 gene. This alteration results from a C to T substitution at nucleotide position 106, causing the arginine (R) at amino acid position 36 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported in a mother and her two children with autosomal dominant spinocerebellar ataxia characterized by early motor delay, poor coordination, gait ataxia, and dysarthria (Casey, 2017). Their study proposed a gain-of -function mechanism of disease that resulted in a higher IP3 binding affinity and enhanced calcium release. The c.106C>T (p.R36C) alteration was also reported in a 10 year old boy with ataxia and hypotonia (Kuperberg, 2016). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002471172	SCV003934823	pathogenic	Spinocerebellar ataxia type 29	2023-05-17	criteria provided, single submitter	clinical testing	Variant summary: ITPR1 c.106C>T (p.Arg36Cys) results in a non-conservative amino acid change located in the Inositol 1,4,5-trisphosphate/ryanodine receptor domain (IPR014821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249140 control chromosomes (gnomAD). c.106C>T has been reported in the literature in individuals affected with clinical symptoms suggestive of Spinocerebellar Ataxia 29 (Kuperberg_2016, Casey_2017, Knuutinen_2021), and in several of these cases the variant occurred de novo. These data indicate that the variant is likely to be associated with disease. One of these publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant resulted in a higher IP3 binding affinity and increased calcium release, suggesting a gain-of-function disease mechanism (Casey_2017). The following publications have been ascertained in the context of this evaluation (PMID: 37164302, 28620721, 27572814, 33948933). Three submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV003987914	SCV004804813	pathogenic	Gillespie syndrome	2023-12-22	criteria provided, single submitter	clinical testing
GeneDx	RCV002051254	SCV005325918	pathogenic	not provided	2023-05-08	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: 30197841, 35621185, 29777722, 28620721, 29906486, 27572814)
OMIM	RCV002471172	SCV002769547	pathogenic	Spinocerebellar ataxia type 29	2023-01-11	no assertion criteria provided	literature only