Submissions for variant NM_001378452.1(ITPR1):c.800C>T (p.Thr267Met)

dbSNP: rs797044955

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000190812	SCV000244253	pathogenic	Inborn genetic diseases	2013-06-27	criteria provided, single submitter	clinical testing
Schule lab, Hertie Institute for Clinical Brain Research	RCV000677366	SCV000700188	pathogenic	Spinocerebellar ataxia type 29	2018-02-09	criteria provided, single submitter	research
Baylor Genetics	RCV000677366	SCV000807309	uncertain significance	Spinocerebellar ataxia type 29	2017-09-01	criteria provided, single submitter	clinical testing	Likely pathogenicity based on finding it once in our laboratory de novo in a 12-year-old female with cerebellar ataxia with tremor (onset in first year of life), significant motor delays, moderate speech delays, hypoplastic cerebellar vermis
GeneDx	RCV001552791	SCV001773550	pathogenic	not provided	2022-01-12	criteria provided, single submitter	clinical testing	Published functional studies suggest ITPR1 loss-of-function (Synofzik et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31632679, 25794864, 24091540, 29925855, 29878067, 28659154, 30842224, 32290556, 30301590, 32695065, 33163565, 27535533)
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001552791	SCV002051641	pathogenic	not provided	2021-01-06	criteria provided, single submitter	clinical testing	PS2, PS3, PS4
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000677366	SCV002512364	pathogenic	Spinocerebellar ataxia type 29	2022-01-23	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM6 moderate, PP3 supporting
MGZ Medical Genetics Center	RCV000677366	SCV002581407	pathogenic	Spinocerebellar ataxia type 29	2021-11-05	criteria provided, single submitter	clinical testing
Invitae	RCV001552791	SCV003525035	pathogenic	not provided	2023-02-14	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 267 of the ITPR1 protein (p.Thr267Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant spinocerebellar ataxia (PMID: 24091540, 31632679). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 208786). 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. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003152595	SCV003841225	pathogenic	Spinocerebellar ataxia type 15/16		criteria provided, single submitter	clinical testing
Genome Medicine, Institute for Basic Research in Developmental Disabilities	RCV000677366	SCV003929451	pathogenic	Spinocerebellar ataxia type 29		criteria provided, single submitter	clinical testing	The variant is classified as “Pathogenic” as per the American College of Medical Genetics (ACMG) guidelines (Richards et al. 2015). Two “Strong” criteria (PS1, PS3) are met as the variant has been previously reported to be pathogenic and there is functional evidence to support a damaging effect on intracellular calcium modulation (Ngo et al. 2019; Ohba et al. 2013; Sasaki et al. 2015; Synofzik et al. 2018; Zambonin et al. 2017; Iwama et al. 2019; Kashimada et al. 2019; Won et al. 2020; Gauquelin et al. 2020; Martínez-Rubio et al. 2022; Romaniello et al. 2022; Zhi et al. 2023). Additionally, the variant meets “Moderate” criteria PM2, given that the variant is not present in GnomAD (Chen et al. 2022). “Supporting” criteria PP3 is also met. The Phred-scaled Combined Annotation Dependent Depletion (CADD) score was calculated to be greater 26.2, which suggests that the pathogenicity of the variant is in the 99.8 percentile (Rentzsch et al. 2019). The Sorting Intolerant From Tolerant (SIFT) and PolyPhen scores also support the variant’s pathogenicity and were calculated to be 0 and 0.994 respectively (Ng and Henikoff 2003; Adzhubei, Jordan, and Sunyaev 2013).
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000677366	SCV004032470	pathogenic	Spinocerebellar ataxia type 29	2023-05-24	criteria provided, single submitter	clinical testing
Department of Rehabilitation Medicine, Chungnam National University Hospital	RCV000677366	SCV004036077	pathogenic	Spinocerebellar ataxia type 29	2022-09-26	no assertion criteria provided	clinical testing	Mutations in the c.800C>T (p.Thr267Met) locus have been documented in the literature for associations with the diagnosis of spinocerebellar ataxia 29. Threonine at position 267 is located at the IRBIT binding region and IP3 binding domain. Variants in the ITPR1 gene have caused loss of function of the IP3R1 protein, thus disrupting calcium release from the endoplasmic reticulum of cells, especially Purkinje cells of the cerebellum, thus causing cerebellar degeneration and characteristics of SCA29.