Submissions for variant NM_001382567.1(STIM1):c.408G>C (p.Glu136Asp)

gnomAD frequency: 0.00009  dbSNP: rs200648767

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000876410	SCV001018978	likely benign	Stormorken syndrome; Combined immunodeficiency due to STIM1 deficiency; Myopathy with tubular aggregates	2024-06-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002540002	SCV003698484	uncertain significance	Inborn genetic diseases	2022-12-19	criteria provided, single submitter	clinical testing	The c.408G>C (p.E136D) alteration is located in exon 4 (coding exon 4) of the STIM1 gene. This alteration results from a G to C substitution at nucleotide position 408, causing the glutamic acid (E) at amino acid position 136 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317395	SCV004020917	uncertain significance	not specified	2023-06-28	criteria provided, single submitter	clinical testing	Variant summary: STIM1 c.408G>C (p.Glu136Asp) results in a conservative amino acid change located in the Sterile alpha motif domain (IPR001660) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 231332 control chromosomes (gnomAD). To our knowledge, no occurrence of c.408G>C in individuals affected with STIM1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely benign, and one as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001355096	SCV004035720	uncertain significance	not provided	2023-03-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Breakthrough Genomics, Breakthrough Genomics	RCV001355096	SCV005223206	likely benign	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355096	SCV001549871	uncertain significance	not provided		no assertion criteria provided	clinical testing	The STIM1 p.Glu136Asp variant was not identified in the literature but was identified in dbSNP (ID: rs200648767) and ClinVar (classified as likely benign by Invitae). The variant was identified in control databases in 41 of 231332 chromosomes at a frequency of 0.0001772 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 33 of 9694 chromosomes (freq: 0.003404), Other in 1 of 5734 chromosomes (freq: 0.000174), African in 1 of 14532 chromosomes (freq: 0.000069), East Asian in 1 of 17434 chromosomes (freq: 0.000057) and European (non-Finnish) in 5 of 104224 chromosomes (freq: 0.000048), but was not observed in the Latino, European (Finnish), or South Asian populations. The p.Glu136 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.