Variant: NM_003593.3:c.1579_1580del

CA2497028946

Gene: FOXN1

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

Inheritance Mode: Semidominant inheritance

UUID: 12815e90-cebc-41e3-b67d-c6495037768c

Approved on: 2024-09-27

Published on: 2024-09-27

HGVS expressions

NM_003593.3:c.1579_1580del
NC_000017.11:g.28535150_28535151del
CM000679.2:g.28535150_28535151del
NC_000017.10:g.26862168_26862169del
CM000679.1:g.26862168_26862169del
NC_000017.9:g.23886295_23886296del
NG_007260.1:g.16210_16211del
ENST00000577936.2:c.1579_1580del
ENST00000579795.6:c.1579_1580del
ENST00000226247.2:c.1579_1580del
ENST00000481916.6:c.*1195+68901_*1195+68902del
ENST00000579795.5:c.1579_1580del
NM_003593.2:c.1579_1580del
NM_001369369.1:c.1579_1580del

Likely Pathogenic

• Met criteria codes: PVS1_Strong PM3_Supporting PM2_Supporting 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 variant NM_001369369.1(FOXN1):c.1579_1580del (p.Thr527Ter) is a nonsense variant predicted to cause a premature stop codon (8/9) and escape nonsense mediated decay. The variant is predicted to remove >10% of the FOXN1 protein and truncate the transactivation domain, a domain important to protein function (PVS1_strong). The variant has been found in at least one homozygous patient with FOXN1 SCID (PM3_supporting, P11, PMIDs: 33464451, 31151968). This patient was whole exome sequenced, and displayed phenotypes including alopecia, nail dystrophy, very low T cell number counts for age, impaired proliferative response to PHA, and low CD8+ T cell number relative to age-matched controls (PP4). The variant is absent from gnomADv4.1 (PM2_supporting). In summary this variant meets criteria to be classified as likely pathogenic for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PVS1_strong, PM2_supporting, PP4, PM3_supporting as specified by the ClinGen SCID VCEP FOXN1 subgroup (Pilot, date of approval xx/xx/2024).

Met criteria codes

• PVS1_Strong: The variant is predicted to cause a stop codon within the last 50 nucleotides of the penultimate exon and thus predicted to escape nonsense mediated decay. It is predicted to remove >10% of the FOXN1 protein and the truncated region is located within the transactivation domain, a domain important to protein function (PVS1_Strong).
• PM3_Supporting: Variant is found in the homozygous state in a patient with FOXN1 SCID.
• PM2_Supporting: The variant is absent from gnomADv4.1.
• PP4: The patient has been reported in a case report PMID: 31151968 and as part of a larger study PMID: 33464451. This patient displayed phenotypes such as alopecia (0.25), nail dystrophy (0.25), and displayed phenotypes such as very low T cell number counts for age and impaired proliferative response to PHA (.25) and low CD8+ T cell number relative to age-matched controls (.25). The patient was also whole exome sequenced (0.5). In total this patient scores 1.5 points for phenotypic points placing them in the PP4 supporting category.