Variant: NM_001369369.1(FOXN1):c.974T>C (p.Leu325Pro)

CA398324519

656631 (ClinVar)

Gene: FOXN1

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

Inheritance Mode: Semidominant inheritance

UUID: 44c9d663-7867-4ab9-9524-ce51847cf206

Approved on: 2024-07-29

Published on: 2024-07-29

HGVS expressions

NM_001369369.1:c.974T>C
NM_001369369.1(FOXN1):c.974T>C (p.Leu325Pro)
NC_000017.11:g.28534377T>C
CM000679.2:g.28534377T>C
NC_000017.10:g.26861395T>C
CM000679.1:g.26861395T>C
NC_000017.9:g.23885522T>C
NG_007260.1:g.15437T>C
ENST00000577936.2:c.974T>C
ENST00000579795.6:c.974T>C
ENST00000226247.2:c.974T>C
ENST00000481916.6:c.*1195+69674A>G
ENST00000579795.5:c.974T>C
NM_003593.2:c.974T>C
NM_003593.3:c.974T>C

Likely Pathogenic

• Met criteria codes: PM1 PP3_Moderate PM2_Supporting PS3_Moderate

• Not Met criteria codes: PP4

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.974T>C (p.Leu325Pro) missense variant has been reported in one heterozygous patient (P22), with T cell lymphopenia, however there was insufficient information to determine specificity to FOXN1-related disease (PMID: 31447097). The highest MAF in gnomADv4.0 is 0.000001313 (1/761890 alleles) in the European (non-Finnish) population which is below the <0.00002412 (PM2_supporting). It has a REVEL score of 0.992 (PP3_Moderate). The missense variant is located within the DNA binding forkhead domain (amino acids 270-367) at amino acid position 325 (PM1). A luciferase reporter construct was cotransfected into heterologous cells together with an expression vector containing FOXN1. The Leu325Pro variant had 2% luciferase activity compared to WT which is below the <50% threshold for PS3_moderate (PMID: 37419334). In summary this variant meets criteria to be classified as likely pathogenic for semidominant cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PM1, PP3_moderate, PS3_moderate, PM2_supporting, as specified by the ClinGen SCID VCEP FOXN1 subgroup.

Met criteria codes

• PM1: The missense variant is located within the DNA binding forkhead domain (amino acids 270-367) at amino acid position 325, and thus meets PM1.
• PP3_Moderate: The variant has a REVEL score of 0.992 which is above the threshold of >0.932 and thus meets PP3_Moderate.
• PM2_Supporting: The highest MAF in gnomADv4.0 is 0.000001313 (1/761890 alleles) in the European (non-Finnish) population which is below the <0.00002412 (PM2_supporting).
• PS3_Moderate: A luciferase reporter construct was cotransfected into heterologous cells together with an expression vector containing FOXN1. The Leu325Pro variant had 2% luciferase activity compared to WT which is below the <50% threshold for PS3_moderate (PMID: 37419334).

Not Met criteria codes

• PP4: A heterozygous patient (P22) was identified with T cell lymphopenia however there was insufficient information to determine specificity to FOXN1-related disease (PMID: 31447097).