Variant: NM_001369369.1(FOXN1):c.1556T>A (p.Leu519Gln)

CA8459559

322433 (ClinVar)

Gene: FOXN1

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

Inheritance Mode: Semidominant inheritance

UUID: e305d2ba-2441-4e8f-9e44-d87b8df864a8

Approved on: 2024-07-29

Published on: 2024-07-29

HGVS expressions

NM_001369369.1:c.1556T>A
NM_001369369.1(FOXN1):c.1556T>A (p.Leu519Gln)
NC_000017.11:g.28535127T>A
CM000679.2:g.28535127T>A
NC_000017.10:g.26862145T>A
CM000679.1:g.26862145T>A
NC_000017.9:g.23886272T>A
NG_007260.1:g.16187T>A
ENST00000577936.2:c.1556T>A
ENST00000579795.6:c.1556T>A
ENST00000226247.2:c.1556T>A
ENST00000481916.6:c.*1195+68924A>T
ENST00000579795.5:c.1556T>A
NM_003593.2:c.1556T>A
NM_003593.3:c.1556T>A

Benign

• Met criteria codes: BA1

• Not Met criteria codes: BP2 BP4 PP4 PP3 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

The variant NM_001369369.1(FOXN1):c.1556T>A is predicted to cause a leucine to glutamine substitution at amino acid position 519. The variant has a Grpmax allele frequency of 0.005940 based upon the gonmADv4.0 African American subpopulation, which is greater than 0.00447 and thus meets BA1 criteria. The meta predictor Revel predicts a score of 0.6, which is less than 0.644 and greater than 0.290, which does not meet BP4 or PP3 criteria. The variant was found in the heterozygous state in P6 from PMID:27484032 who displayed phenotypes such as low TRECs on NBS, severe T cell lymphopenia, and was sequenced via NGS for 46 PIDD genes. Notably this patient did not display phenotypes such as alopecia or nail dystrophy. This patient also carried a pathogenic variant p.Arg320Trp in the heterozygous state, with unknown phasing. In summary this variant meets criteria to be classified as benign for semidominant cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: BA1 as specified by the ClinGen SCID VCEP FOXN1 subgroup.

Met criteria codes

• BA1: The variant has a popmax filtering allele frequency of 0.005940 based upon the African American subpopulation in gnomAD v4.0. This is greater than the threshold for BA1 >0.00447, and thus meets BA1 criteria. Notably there were two homozygous individuals reported with the variant in gnomAD v4.0.

Not Met criteria codes

• BP2: One patient P6 individual with T cell lymphopenia and low TRECs was reported with the pathogenic variant p.Arg320Trp (unknown phasing).
• BP4: The meta predictor revel predicts a score of 0.6, which is less than 0.644 and greater than .290, which does not meet BP4 or PP3 criteria.
• PP4: P6 from PMID: 27484032 displayed phenotypes such as low TRECs on NBS (0.25), severe T cell lymphopenia (0.25), and was sequenced via NGS for 46 PIDD genes (0.5 points), total of 1 point. Not considered here because variant meets BA1.
• PP3: The meta predictor revel predicts a score of 0.6, which is less than 0.644 and greater than .290, which does not meet BP4 or PP3 criteria.
• PM3: One patient P6 individual with T cell lymphopenia and low TRECs was reported with the pathogenic variant p.Arg320Trp (unknown phasing). Not considered because this variant meets BA1.