Submissions for variant NM_001382567.1(STIM1):c.661G>A (p.Val221Ile)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003076600	SCV003450088	uncertain significance	Stormorken syndrome; Combined immunodeficiency due to STIM1 deficiency; Myopathy with tubular aggregates	2023-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 221 of the STIM1 protein (p.Val221Ile). This variant is present in population databases (rs186158674, gnomAD 0.01%). 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: 2143190). 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV003340604	SCV004048140	uncertain significance	Myopathy, tubular aggregate, 1		criteria provided, single submitter	clinical testing	The missense variant p.V221I in STIM1 (NM_003156.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. There is a small physicochemical difference between valine and isoleucine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.V221I missense variant is predicted to be damaging by both SIFT and PolyPhen2. The valine residue at codon 221 of STIM1 is conserved in all mammalian species. The nucleotide c.661 in STIM1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Ambry Genetics	RCV004070296	SCV004960045	uncertain significance	Inborn genetic diseases	2024-02-13	criteria provided, single submitter	clinical testing	The c.661G>A (p.V221I) alteration is located in exon 6 (coding exon 6) of the STIM1 gene. This alteration results from a G to A substitution at nucleotide position 661, causing the valine (V) at amino acid position 221 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.