Variant: NM_001369369.1(FOXN1):c.763C>T (p.Arg255Ter)

CA119892

8757 (ClinVar)

Gene: FOXN1

Condition: T-cell immunodeficiency, congenital alopecia, and nail dystrophy

Inheritance Mode: Semidominant inheritance

UUID: 978177f0-10ea-4f24-816b-9260142ade71

Approved on: 2024-07-29

Published on: 2024-07-29

HGVS expressions

NM_001369369.1:c.763C>T
NM_001369369.1(FOXN1):c.763C>T (p.Arg255Ter)
NC_000017.11:g.28529157C>T
CM000679.2:g.28529157C>T
NC_000017.10:g.26856175C>T
CM000679.1:g.26856175C>T
NC_000017.9:g.23880302C>T
NG_007260.1:g.10217C>T
ENST00000577936.2:c.763C>T
ENST00000579795.6:c.763C>T
ENST00000226247.2:c.763C>T
ENST00000481916.6:c.*1196-73048G>A
ENST00000579795.5:c.763C>T
NM_003593.2:c.763C>T
NM_003593.3:c.763C>T

Pathogenic

• Met criteria codes: PVS1 PP4 PM3 PP1_Strong PM2_Supporting

Expert Panel

Severe Combined Immunodeficiency Disease VCEP

Criteria Specification Information

Criteria Specification: ClinGen Severe Combined Immunodeficiency Disease Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for FOXN1 Version 1.0.0

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NM_001369369.1(FOXN1):c.763C>T (p.Arg255Ter) nonsense variant occurs in exon 5 of 9 and is predicted to result in non-sense mediated decay (PVS1). The highest MAF in gnomAD v2.1.1 is 0.000008790 (1/113762 alleles) in the European (non-Finnish) population. This is below the SCID VCEP specified threshold of <0.00002412 (PM2_supporting). At least one patient (PMID: 10206641) is described with congenital alopecia, nail dystrophy, and very low T cell number which is highly specific to FOXN1 deficiency (PP4). This individual had an affected siblings, also homozygous for the variant, as reported in PMID: 10206641. Additionally PMID: 31447097 reports another 14 heterozygous relatives with nail dystrophy belonging to same extended family (estimated LOD score 4.82; PP1_Strong). At least two additional unrelated patients have been reported, these three unrelated patients are all homozygous (PMIDs: 28636882, 20978268, 10206641; PM3). In summary this variant meets criteria to be classified as pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1, PM2_supporting, PP4, PP1_strong, PM3 as specified by the ClinGen SCID VCEP FOXN1 subgroup (specifications v1.0).

Met criteria codes

• PVS1: The nonsense variant occurs in exon 5 of 9 and is predicted to result in NMD.
• PP4: At least one patient (PMID: 10206641) is described with congenital alopecia (0.25pt), nail dystrophy (0.25pt), and very low T cell number of 25/ul CD3+ (0.5pt). Total 1pt (PP4)
• PM3: At least three unrelated homozygous patients have been reported (PMIDs: 28636882, 20978268, 10206641) with specific phenotypes but only PMID: 28636882 reported exome sequencing 1pt+0.5pt+0.5pt=2pt (PM3).
• PP1_Strong: A proband plus an affected sibling are both homozygous for the variant, as reported in PMID: 10206641. Additionally PMID: 31447097 reports another 14 heterozygous individuals with nail dystrophy belonging to the same extended pedigree. Z=log(1/[0.25^1x0.5^14])=4.82 (PP1_Strong)
• PM2_Supporting: The GrpMax in gnomADv4.0 is 0.0000002800 (based on 2/1180014 alleles) in the European (non-Finnish) population. This is below the SCID VCEP specified threshold of <0.00002412 (PM2_supporting).