Submissions for variant NM_032790.4(ORAI1):c.100A>C (p.Ser34Arg)

gnomAD frequency: 0.00102  dbSNP: rs781829024

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000652295	SCV000774163	uncertain significance	Combined immunodeficiency due to ORAI1 deficiency; Myopathy, tubular aggregate, 2	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 34 of the ORAI1 protein (p.Ser34Arg). This variant is present in population databases (rs781829024, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ORAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 541941). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects ORAI1 function (PMID: 31036819). 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.
GeneDx	RCV000836176	SCV000978007	likely benign	not provided	2018-04-24	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CeGaT Center for Human Genetics Tuebingen	RCV000836176	SCV001334790	uncertain significance	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000652295	SCV001468432	uncertain significance	Combined immunodeficiency due to ORAI1 deficiency; Myopathy, tubular aggregate, 2	2020-06-30	criteria provided, single submitter	clinical testing	ORAI1 NM_032790.3 exon 1 p.Ser34Arg (c.100A>C): This variant has not been reported in the literature in association with human disease, but is present in 0.1% (71/52582) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/12-122064747-A-C?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:541941). Evolutionary conservation suggests that this variant may impact the protein; computational predictive tools suggest that this variant may not impact the protein. In vitro functional studies predict that this variant will impact the protein (Zhang 2019 PMID:31036819). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Baylor Genetics	RCV001336793	SCV001530288	uncertain significance	Combined immunodeficiency due to ORAI1 deficiency	2018-04-18	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GenomeConnect - Invitae Patient Insights Network	RCV000652295	SCV001749978	not provided	Combined immunodeficiency due to ORAI1 deficiency; Myopathy, tubular aggregate, 2		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 02-15-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.