Variant: NM_001369369.1(FOXN1):c.246C>A (p.Cys82Ter)

CA398320910

2780381 (ClinVar)

Gene: FOXN1

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

Inheritance Mode: Semidominant inheritance

UUID: 7b2de6b9-9cde-4011-afe0-6bf5073780e9

Approved on: 2024-09-27

Published on: 2025-02-20

HGVS expressions

NM_001369369.1:c.246C>A
NM_001369369.1(FOXN1):c.246C>A (p.Cys82Ter)
NC_000017.11:g.28524625C>A
CM000679.2:g.28524625C>A
NC_000017.10:g.26851643C>A
CM000679.1:g.26851643C>A
NC_000017.9:g.23875770C>A
NG_007260.1:g.5685C>A
ENST00000577936.2:c.246C>A
ENST00000579795.6:c.246C>A
ENST00000226247.2:c.246C>A
ENST00000481916.6:c.*1196-68516G>T
ENST00000577936.1:c.246C>A
ENST00000579795.5:c.246C>A
NM_003593.2:c.246C>A
NM_003593.3:c.246C>A

Pathogenic

• Met criteria codes: PVS1 PP4 PM2_Supporting

• Not Met criteria codes: PM3

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

NM_001369369.1(FOXN1):c.246C>A (p.Cys82Ter) is a nonsense variant predicted to cause a premature stop codon (3/9) and lead to nonsense mediated decay in a disease that is loss of function (PVS1). The variant has been found in at least one compound heterozygous patient with FOXN1 deficiency (P9, PMID: 33464451). The patient displayed alopecia and low t-cell numbers (less than 1,000,000 cells/L) (PP4). They also had poor proliferative response to phytohemagglutinin on total cells, though normal when evaluated on separated T cells, flow cytometric analysis showed near complete absence of CD45RA+ CD4 T cells, and they had very low TRECs. They received a thymus transplant but T cell levels were not reported post transplant. Interestingly the patients alopecia spontaneously reversed at age 3. The variant is absent from gnomADv4.1 (PM2_supporting). 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 as specified by the ClinGen SCID VCEP FOXN1 subgroup (Pilot, date of approval xx/xx/2024).

Met criteria codes

• PVS1: The NM_001369369.1:c.246C>A (p.Cys82Ter) variant in FOXN1 is a nonsense variant that is predicted to cause a premature stop codon in biologically relevant exon 3/9 that leads to nonsense-mediated decay in a gene in which loss-of-function is an established mechanism (PVS1).
• PP4: At least one patient (P9 of PMID: 33464451) with this variant displayed alopecia (0.25 pts) and low t-cell numbers (less than 1,000,000 cells/L; 0.5pts). The patient had whole exome sequencing (0.5pt) Total 1.25pt (PP4). The patient also had poor proliferative response to phytohemagglutinin on total cells, while it was normal when evaluated on separated T cells, flow cytometric analysis showed near complete absence of CD45RA+ CD4 T cells, and they had very low TRECs. They received a thymus transplant but T cell levels were not reported post transplant. Interestingly the patients alopecia spontaneously reversed at age 3.
• PM2_Supporting: This variant is absent from gnomAD v4.1 (PM2_Supporting).

Not Met criteria codes

• PM3: the patient is compound heterozygous with likely pathogenic variant NM_001369369.1(FOXN1):c.1049C>T (p.Pro350Leu), confirmation of trans phase not reported. Not considered here to avoid circularity.