Submissions for variant NM_014009.4(FOXP3):c.1010G>A (p.Arg337Gln)

dbSNP: rs2066044949

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001204541	SCV001375751	likely pathogenic	Insulin-dependent diabetes mellitus secretory diarrhea syndrome	2019-09-13	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individuals with clinical features of IPEX syndrome (PMID: 18931102, 30443250, 24982679, 25911531, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 337 of the FOXP3 protein (p.Arg337Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV001204541	SCV001445930	pathogenic	Insulin-dependent diabetes mellitus secretory diarrhea syndrome	2019-09-25	criteria provided, single submitter	clinical testing	This variant has been previously reported as a hemizygous change in patients with Immunodysregulation, Polyendocrinopathy, and Enteropathy, X-Linked (IPEX) Syndrome (PMID: 18931102, 24982679, 28289675, 29241729, 30443250). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. The c.1010G>A (p.Arg337Gln) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1010G>A (p.Arg337Gln) variant is classified as Pathogenic.
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV001204541	SCV001499933	pathogenic	Insulin-dependent diabetes mellitus secretory diarrhea syndrome	2020-12-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001204541	SCV002570853	pathogenic	Insulin-dependent diabetes mellitus secretory diarrhea syndrome	2022-07-18	criteria provided, single submitter	clinical testing	Variant summary: FOXP3 c.1010G>A (p.Arg337Gln) results in a conservative amino acid change located in the Fork head domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 180275 control chromosomes. c.1010G>A has been reported in the literature in individuals affected with Insulin-Dependent Diabetes Mellitus Secretory Diarrhea Syndrome. These data indicate that the variant may be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV001204541	SCV002605323	likely risk allele	Insulin-dependent diabetes mellitus secretory diarrhea syndrome		criteria provided, single submitter	research	Potent mutations in FOXP3 gene are associated with a rare X linked condition called IPEX. It presents with immune dysregulation, secretory diarrhea, polyendocrinopathy which includes diabtes type 1, thyroiditis, growth hormone deficiency and hypoadrenalism. It is associated with pancreatic beta cell destruction.However no sufficient evidence is found to ascertain the role of this particular variant rs2066044949, yet.
Athena Diagnostics	RCV002504237	SCV002817280	pathogenic	not provided	2019-08-21	criteria provided, single submitter	clinical testing	This variant was reported to be maternally inherited in multiple patients with clinical features of IPEX (PMID: 18931102, 27167055, 28289675, 24982679, 23771172, 28488220, 25911531, 30951839, 30443250). This variant appears to have occurred de novo in one mother of an affected patient (PMID: 28289675). This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools yielded predictions that this amino acid change may be damaging to the protein. This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV003389067	SCV004101228	pathogenic	Neurodevelopmental disorder	2023-02-14	criteria provided, single submitter	clinical testing