Variant: NM_001369369.1(FOXN1):c.814C>A (p.Pro272Thr)

CA398323326

1496514 (ClinVar)

Gene: FOXN1

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

Inheritance Mode: Semidominant inheritance

UUID: 69aac4c0-7afe-4773-996d-b92d60c36dbb

Approved on: 2025-04-25

Published on: 2025-04-25

HGVS expressions

NM_001369369.1:c.814C>A
NM_001369369.1(FOXN1):c.814C>A (p.Pro272Thr)
NC_000017.11:g.28529208C>A
CM000679.2:g.28529208C>A
NC_000017.10:g.26856226C>A
CM000679.1:g.26856226C>A
NC_000017.9:g.23880353C>A
NG_007260.1:g.10268C>A
ENST00000577936.2:c.814C>A
ENST00000579795.6:c.814C>A
ENST00000226247.2:c.814C>A
ENST00000481916.6:c.*1196-73099G>T
ENST00000579795.5:c.814C>A
NM_003593.2:c.814C>A
NM_003593.3:c.814C>A

Likely Pathogenic

• Met criteria codes: PP3_Moderate PM2_Supporting PP4 PM1 PM3_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:c.814C>A variant in FOXN1 is a missense variant predicted to cause substitution of proline by threonine at amino acid 74 (p.Pro272Thr). The variant is absent from gnomAD v4.1.0 (PM2_Supporting). The variant was observed in one patient who was homozygous for this variant (PMID 35064468) (PM3_Supporting). The patient presented with alopecia universalis, nail dystrophy, and T-B-NK+ lymphocyte counts (CD3+, 489 cells/μL; CD4+, 295 cells/μL; CD8+, 164 cells/μL; CD19+, 373 cells/μL; CD16+56+, 3978 cells/μL). No other variant of interest was reported from a PID gene panel of 407 genes (PP4). The variant resides within the DNA binding forkhead domain (amino acids 270-367) that is defined as a critical functional domain of FOXN1 with low tolerance for benign variation (PM1_Moderate). The REVEL score for this variant is 0.939, also supporting a deleterious effect on the protein function (PP3_Moderate). In summary, this variant is classified as a likely pathogenic variant for SCID. ACMG/AMP criteria applied, as specified by the ClinGen SCID-VCEP: PM2_Supporting, PM3_Supporting, PP4, PM1, PP3_Moderate. (VCEP specifications version 1.0.0)

Met criteria codes

• PP3_Moderate: The REVEL score for this variant is 0.939, which is higher than the SCID VCEP's threshold (>0.932) for PP3_Moderate. PP3_Moderate is met.
• PM2_Supporting: This variant is absent from gnomAD v4.1.0. PM2_Supporting is met.
• PP4: The variant was observed in one patient with SCID (PMID 35064468). The patient presented with alopecia universalis (0.25pt) and nail dystrophy (0.25pt) since birth. Lymphocyte subpopulation showed low T cell (CD3+, 489 cells/μL; CD4+, 295 cells/μL; CD8+, 164 cells/μL) and B cell (CD19+, 373 cells/μL) counts, and high NK cell counts (CD16+56+, 3978 cells/μL) (0.5pt). No other variant of interest was reported from a PID gene panel of 407 genes (0.5pt). 1.5pt for PP4, PP4 is met.
• PM1: This variant resides within the DNA binding forkhead domain (amino acids 270-367) that is defined as a critical functional domain of FOXN1 with low tolerance for benign variation. (PM1_Moderate)
• PM3_Supporting: The variant was observed in one patient who was homozygous for this variant. The patient presented with phenotype specific with gene (meets PP4) and no other variant of interest was reported from an PID panel of 407 immunity genes. 1pt for PM3, PM3_Supporting is met.