Submissions for variant NM_014009.4(FOXP3):c.152G>A (p.Arg51Gln)

gnomAD frequency: 0.00004  dbSNP: rs1170772176

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001806840	SCV002051407	uncertain significance	not specified	2021-12-28	criteria provided, single submitter	clinical testing	Variant summary: FOXP3 c.152G>A (p.Arg51Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 113449 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.152G>A has been reported in the literature as a non-informative genotype (second allele/zygosity not specified) in at-least one individual from a cohort affected with Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome (example, Duclaux-Loras_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Insulin-Dependent Diabetes Mellitus Secretory Diarrhea Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV002503296	SCV002781672	uncertain significance	Insulin-dependent diabetes mellitus secretory diarrhea syndrome	2021-10-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002503296	SCV003461840	uncertain significance	Insulin-dependent diabetes mellitus secretory diarrhea syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 51 of the FOXP3 protein (p.Arg51Gln). 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. 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 FOXP3 protein function. ClinVar contains an entry for this variant (Variation ID: 1331496). This missense change has been observed in individual(s) with IPEX syndrome (PMID: 30385752). This variant is not present in population databases (gnomAD no frequency).
PreventionGenetics, part of Exact Sciences	RCV003401725	SCV004104580	uncertain significance	FOXP3-related disorder	2023-03-15	criteria provided, single submitter	clinical testing	The FOXP3 c.152G>A variant is predicted to result in the amino acid substitution p.Arg51Gln. This variant was reported in an individual with IPEX syndrome (Duclaux-Loras et al 2018. PubMed ID: 30385752). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.