Submissions for variant NM_014009.4(FOXP3):c.748_750del (p.Lys250del)

dbSNP: rs1557116163

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000595405	SCV000705614	likely pathogenic	not provided	2017-03-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380271	SCV001578271	pathogenic	Insulin-dependent diabetes mellitus secretory diarrhea syndrome	2021-08-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect FOXP3 protein function (PMID: 16920951, 17586580). This variant has been observed in individual(s) with clinical features of immunodysregulation, polyendocrinopathy, and enteropathy (IPEX) syndrome (PMID: 29907148, 19189134, 12161590, 30443250, Invitae). This variant is also known as delE251. ClinVar contains an entry for this variant (Variation ID: 499890). This variant is not present in population databases (ExAC no frequency). This variant, c.748_750del, results in the deletion of 1 amino acid(s) of the FOXP3 protein (p.Lys250del), but otherwise preserves the integrity of the reading frame.
Neuberg Centre For Genomic Medicine, NCGM	RCV001380271	SCV004100522	pathogenic	Insulin-dependent diabetes mellitus secretory diarrhea syndrome		criteria provided, single submitter	clinical testing	The in-frame deletion p.K250del in FOXP3 (NM_014009.4) has been observed in multiple affected individuals with IPEX syndrome (Gambineri E et al,Wildin RS et al,Hashimura Y et al). The variant has been submitted to ClinVar as Pathogenic.The p.K250del variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant results in a deletion of a lysine at position 250 of the FOXP3 gene. However, as this is an in-frame deletion, it is not expected to result in either a truncated protein product or loss of protein through nonsense-mediated mRNA decay. The nucleotide c.748 in FOXP3 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV001380271	SCV002605326	likely benign	Insulin-dependent diabetes mellitus secretory diarrhea syndrome		flagged submission	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 rs1557116163, yet.