Submissions for variant NM_001378452.1(ITPR1):c.7082C>T (p.Thr2361Met)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV003366817	SCV004073181	uncertain significance	Inborn genetic diseases	2023-06-16	criteria provided, single submitter	clinical testing	The c.6893C>T (p.T2298M) alteration is located in exon 50 (coding exon 48) of the ITPR1 gene. This alteration results from a C to T substitution at nucleotide position 6893, causing the threonine (T) at amino acid position 2298 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994541	SCV004813906	uncertain significance	not specified	2024-02-12	criteria provided, single submitter	clinical testing	Variant summary: ITPR1 c.6893C>T (p.Thr2298Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249212 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6893C>T in individuals affected with Spinocerebellar Ataxia 29 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2604499). Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005104129	SCV005787054	uncertain significance	not provided	2024-04-04	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 2298 of the ITPR1 protein (p.Thr2298Met). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with ITPR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2604499). 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 with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.