Submissions for variant NM_014009.4(FOXP3):c.1222G>A (p.Val408Met)

dbSNP: rs1557115532

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000504127	SCV000594877	likely pathogenic	Insulin-dependent diabetes mellitus secretory diarrhea syndrome	2017-02-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000504127	SCV001205631	pathogenic	Insulin-dependent diabetes mellitus secretory diarrhea syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 408 of the FOXP3 protein (p.Val408Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of IPEX syndrome, congenital enteropathy, and/or neonatal diabetes (PMID: 18931102, 30443250, 30894704, 32279225, 33833438, 34216291). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 435255). 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 expected to disrupt FOXP3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000504127	SCV002511796	likely pathogenic	Insulin-dependent diabetes mellitus secretory diarrhea syndrome	2022-04-29	criteria provided, single submitter	clinical testing	Variant summary: FOXP3 c.1222G>A (p.Val408Met) 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 182058 control chromosomes. c.1222G>A has been reported in the literature in individuals affected with Insulin-Dependent Diabetes Mellitus Secretory Diarrhea Syndrome. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003392329	SCV004119226	likely pathogenic	FOXP3-related disorder	2022-08-28	criteria provided, single submitter	clinical testing	The FOXP3 c.1222G>A variant is predicted to result in the amino acid substitution p.Val408Met. This variant was reported in individuals with neonatal diabetes and/or IPEX syndrome (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) (Rubio-Cabezas et al. 2009. PubMed ID: 18931102; Gambineri et al. 2018. PubMed ID: 30443250; Supplementary Table 1, Ye et al. 2019. PubMed ID: 30894704; Cao et al. 2020. PubMed ID: 32279225; Zemmour et al. 2021. PubMed ID: 33833438). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.