Submissions for variant NM_001382567.1(STIM1):c.458C>T (p.Thr153Ile)

gnomAD frequency: 0.00022  dbSNP: rs144602692

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526622	SCV000634552	uncertain significance	Stormorken syndrome; Combined immunodeficiency due to STIM1 deficiency; Myopathy with tubular aggregates	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 153 of the STIM1 protein (p.Thr153Ile). This variant is present in population databases (rs144602692, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with STIM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 461734). 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 not expected to disrupt STIM1 protein function with a negative 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.
New York Genome Center	RCV001291831	SCV001480456	uncertain significance	Combined immunodeficiency due to STIM1 deficiency	2020-06-05	criteria provided, single submitter	clinical testing
GeneDx	RCV002260646	SCV002540285	uncertain significance	not provided	2022-06-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in both affected and unaffected individuals in a case-control study of patients with pancreatitis (Masson et al., 2019).; This variant is associated with the following publications: (PMID: Masson2019[casereport], 33468626)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV002260646	SCV003799983	uncertain significance	not provided	2022-03-17	criteria provided, single submitter	clinical testing
New York Genome Center	RCV003448319	SCV004176083	uncertain significance	Myopathy, tubular aggregate, 1	2023-04-21	criteria provided, single submitter	clinical testing	The c.458C>T variant in STIM1 has not previously been reported in the literature in individuals affected with STIM1-related conditions but it has been deposited in ClinVar as Variant of Uncertain Significance by multiple submitters [ClinVar ID: 461734]. The c.458C>T variant is observed in 171 alleles (~0.022% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases, however, it is uncertain whether this frequency is higher than the disease prevalence or there might be individuals with subtle and slowly progressing symptoms among the variant carriers in those databases. The c.458C>T variant in STIM1 is located in exon 4 of this 12-exon gene and predicted to replace a moderately conserved threonine amino acid with isoleucine at position 153 in the SAM domain of the encoded protein. In silico predictions are not in favor of damaging effect for the p.(Thr153Ile) variant [(CADD v1.6 = 23, REVEL =0.328)]. In vitro studies conducted with this variant are inconclusive [PMID:33468626]. Based on available evidence this c.458C>T p.(Thr153Ile) variant identified in STIM1 is classified as a Variant of Uncertain Significance.
Breakthrough Genomics, Breakthrough Genomics	RCV002260646	SCV005191129	uncertain significance	not provided		criteria provided, single submitter	not provided