NM_014009.4(FOXP3):c.1010G>A (p.Arg337Gln) AND Insulin-dependent diabetes mellitus secretory diarrhea syndrome

Germline classification:: Pathogenic/Likely pathogenic/Likely risk allele (5 submissions)
Last evaluated:: Jul 18, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001204541.11

Allele description [Variation Report for NM_014009.4(FOXP3):c.1010G>A (p.Arg337Gln)]

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

Gene:

FOXP3:forkhead box P3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xp11.23

Genomic location:

Preferred name:

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

HGVS:

NC_000023.11:g.49253160C>T
NG_007392.1:g.16668G>A
NG_021311.2:g.22696C>T
NM_001114377.2:c.905G>A
NM_014009.4:c.1010G>AMANE SELECT
NP_001107849.1:p.Arg302Gln
NP_054728.2:p.Arg337Gln
LRG_62t1:c.1010G>A
LRG_62:g.16668G>A
NC_000023.10:g.49109621C>T
NM_014009.3:c.1010G>A

Protein change:

R302Q

Links:

dbSNP: rs2066044949

NCBI 1000 Genomes Browser:

rs2066044949

Molecular consequence:

NM_001114377.2:c.905G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_014009.4:c.1010G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Insulin-dependent diabetes mellitus secretory diarrhea syndrome (IPEX)
Synonyms:: DIABETES MELLITUS, CONGENITAL INSULIN-DEPENDENT, WITH FATAL SECRETORY DIARRHEA; IMMUNODEFICIENCY, POLYENDOCRINOPATHY, AND ENTEROPATHY, X-LINKED; X-linked autoimmunity-allergic dysregulation syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010580; MedGen: C0342288; Orphanet: 37042; OMIM: 304790

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001375751	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 13, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18931102, 30443250, 24982679, 25911531, 28492532
SCV001445930	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 25, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001499933	Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 20, 2020)	de novo	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24982679, 28289675, 25741868
SCV002570853	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 18, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18931102, 32531870, 27167055 Citation Link,
SCV002605323	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	criteria provided, single submitter (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)	Likely risk allele	unknown	research	PubMed (5) [See all records that cite these PMIDs] 29193502, 33194927, 11137993, 23313429, 33523441 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	research
East Asia	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome.

Gambineri E, Ciullini Mannurita S, Hagin D, Vignoli M, Anover-Sombke S, DeBoer S, Segundo GRS, Allenspach EJ, Favre C, Ochs HD, Torgerson TR.

Front Immunol. 2018;9:2411. doi: 10.3389/fimmu.2018.02411.

PubMed [citation]

PMID:: 30443250
PMCID:: PMC6223101

Renal involvement in the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder.

Sheikine Y, Woda CB, Lee PY, Chatila TA, Keles S, Charbonnier LM, Schmidt B, Rosen S, Rodig NM.

Pediatr Nephrol. 2015 Jul;30(7):1197-202. doi: 10.1007/s00467-015-3102-x. Epub 2015 Apr 25.

PubMed [citation]

PMID:: 25911531

See all PubMed Citations (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001375751.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV001445930.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital, SCV001499933.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asia	1	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	de novo	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002570853.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic, SCV002605323.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1		not provided	not provided	not provided	research	PubMed (5)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine