Variant: NM_003593.3:c.1168del

CA2497028945

Gene: FOXN1

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

Inheritance Mode: Semidominant inheritance

UUID: d08cc36c-82e7-41b0-af27-3435e46219d4

Approved on: 2024-07-29

Published on: 2024-07-29

HGVS expressions

NM_003593.3:c.1168del
NC_000017.11:g.28534739del
CM000679.2:g.28534739del
NC_000017.10:g.26861757del
CM000679.1:g.26861757del
NC_000017.9:g.23885884del
NG_007260.1:g.15799del
ENST00000577936.2:c.1168del
ENST00000579795.6:c.1168del
ENST00000226247.2:c.1168del
ENST00000481916.6:c.*1195+69312del
ENST00000579795.5:c.1168del
NM_003593.2:c.1168del
NM_001369369.1:c.1168del

Likely Pathogenic

• Met criteria codes: PP4 PM2_Supporting PVS1_Strong

• Not Met criteria codes: PP1

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.1168del (p.Glu390LysfsTer?) frameshift variant in exon 8 results in a premature stop codon in the final exon (exon 9) at codon 550. It is not predicted to cause NMD but would truncate 16% of the protein, including most of the transactivation domain which is critical to protein function (PVS1_Strong). The variant is absent from gnomADv4.0 (PM2_Supporting). At least one heterozygous patient has been reported with nail dystrophy, low T cell count for age 1.0x10^9/L, and low TRECs (P8 from PMID: 31447097, PP4). The patient was also described to have recurrent severe infections. This patient's mother, P30 carried the same variant and was noted to have nail dystrophy. 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, and PP4, as specified by the ClinGen SCID VCEP FOXN1 subgroup.

Met criteria codes

• PP4: This variant has been identified in one patient P8 in the heterozygous state from PMID: 31447097. P8 displayed phenotypes such as nail dystrophy (0.25), low T cell count for age 1.0x10^9/L, (.25), and low TRECs (.25). Patient was also noted to have recurrent severe infections. The patient was sequenced for other SCID related genes (0.5). In total this patient scores 1.25 points for phenotypic points placing them in the PP4 supporting category.
• PM2_Supporting: The variant is absent from gnomADv4.1.
• PVS1_Strong: The variant NM_001369369.1(FOXN1):c.1168del (p.Glu390LysfsTer?) is a frameshift variant in exon 8/9 that is predicted to escape nonsense mediated decay but truncate/alter the transactivation domain, a domain critical to protein function.

Not Met criteria codes

• PP1: This patient's mother, P30 who also carried the frameshift variant, also reported nail dystrophy and recurrent respiratory infections (PMID: 31447097). Insufficient for PP1.