Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001369369.1(FOXN1):c.880G>C (p.Val294Leu)

CA398323707

644342 (ClinVar)

Gene: FOXN1 (HGNC:8456)

Condition: T-cell immunodeficiency, congenital alopecia, and nail dystrophy (MONDO:0011132)

Inheritance Mode: Semidominant inheritance

UUID: 1a17ad23-4a69-49ba-94f0-ea6d369b6360

Approved on: 2024-07-29

Published on: 2024-07-29

HGVS expressions

NM_001369369.1(FOXN1):c.880G>C (p.Val294Leu)

NM_001369369.1:c.880G>C

NC_000017.11:g.28530798G>C

CM000679.2:g.28530798G>C

NC_000017.10:g.26857816G>C

CM000679.1:g.26857816G>C

NC_000017.9:g.23881943G>C

NG_007260.1:g.11858G>C

ENST00000577936.2:c.880G>C

ENST00000579795.6:c.880G>C

ENST00000226247.2:c.880G>C

ENST00000481916.6:c.*1195+73253C>G

ENST00000579795.5:c.880G>C

NM_003593.2:c.880G>C

NM_003593.3:c.880G>C

Likely Pathogenic

PM1 PS3_Moderate PM2_Supporting PP3

PM5 PS4 PP4

Evidence Links 1

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Severe Combined Immunodeficiency Disease VCEP

The NM_001369369.1(FOXN1):c.880G>C (p.Val294Leu) missense variant is located within the DNA binding forkhead domain (amino acids 270-367) at amino acid position 294, and thus meets PM1. The variant has a REVEL score of 0.68 which is above the SCID VCEP specified threshold of ≥0.644 to support a deleterious effect of the variant (PP3). The variant is absent from gonmADv2.1.1 (PM2_supporting). A comprehensive literature search, did not identify the variant in any individuals with T-cell immunodeficiency, congenital alopecia, and nail dystrophy, however personal communication with Invitae confirmed the variant has been observed in one neonate with low TRECs. A luciferase reporter construct was cotransfected into heterologous cells together with an expression vector containing FOXN1. This variant had 13.5% 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 T-cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PM1, PM2_supporting, PS3_Moderate, and PP3, as specified by the ClinGen SCID VCEP FOXN1 subgroup.

PM1

The missense variant is located within the DNA binding forkhead domain (amino acids 270-367) at amino acid position 294, and thus meets PM1.

PS3_Moderate

A luciferase reporter construct was cotransfected into heterologous cells together with an expression vector containing FOXN1. This variant had 13.5% luciferase activity compared to WT, which is below the <50% threshold for PS3_moderate (PMID: 37419334).

PM2_Supporting

The variant is absent from gonmADv4.0 (PM2_supporting).

PP3

The variant has a REVEL score of 0.68 which is above the SCID VCEP specified threshold of ≥0.644 to support a deleterious effect of the variant (PP3).

PM5

This variant occurs at the same codon as a previously identified variant, NM_001369369.1(FOXN1):c.880G>A (p.Val294Ile), which has been classified Pathogenic by the SCID VCEP. It is not considered here to avoid circularity.

PS4

The variant has been seen in one patient, by Invitae, with low TRECs (0.25pt; insufficient for PS4)

PP4

Invitae patient with low TRECs (insufficient to apply PP4).

Curation History

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