Evidence Repository - GenboreeKB

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.933_936dup (p.Asp313fs)

CA915949637

827574 (ClinVar)

Gene: FOXN1 (HGNC:8456)

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

Inheritance Mode: Semidominant inheritance

UUID: 3fee475c-7628-4c86-a0c7-ffcd348b9fe7

Approved on: 2024-07-29

Published on: 2024-07-29

HGVS expressions

NM_001369369.1:c.933_936dup

NM_001369369.1(FOXN1):c.933_936dup (p.Asp313fs)

NC_000017.11:g.28534336_28534339dup

CM000679.2:g.28534336_28534339dup

NC_000017.10:g.26861354_26861357dup

CM000679.1:g.26861354_26861357dup

NC_000017.9:g.23885481_23885484dup

NG_007260.1:g.15396_15399dup

ENST00000577936.2:c.933_936dup

ENST00000579795.6:c.933_936dup

ENST00000226247.2:c.933_936dup

ENST00000481916.6:c.*1195+69713_*1195+69716dup

ENST00000579795.5:c.933_936dup

NM_003593.2:c.933_936dup

NM_003593.3:c.933_936dup

Pathogenic

PP4 PM2_Supporting PVS1

PS3 PS4 PM3

Evidence Links 0

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.933_936dup (p.Asp313ThrfsTer?) frameshift variant in exon 7, of 9, results in a premature stop codon in exon 8, which is predicted to cause NMD (PVS1). The variant was detected by exome sequencing with Sanger confirmation in one patient (Pt 1) who is compound heterozygous with c.1089_1103del (PMID: 31566583). The patient has normal hair and nails but T-B+NK+ SCID. They had Undetectable TRECs, at 3 months there were low CD3 31 cells/uL (0.5pt), and CD8 3 cells/uL, with NK 188 cells/uL, CD19+ 2159 cells/uL (PP4). 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, and PP4 as specified by the ClinGen SCID VCEP FOXN1 subgroup.

PP4

The variant was detected by exome sequencing with Sanger confirmation in one patient (Pt 1) with normal hair and nails but T-B+NK+ SCID. They had Undetectable TRECs, at 3 months CD3 31 cells/uL (2500-5500) (0.5pt), CD8 3 (500-1700), NK 188 (170-1100), CD19+ 2159 (300-2000), (PMID: 31566583; PP4).

PM2_Supporting

This variant is absent from gnomADv4.0 (PM2_supporting).

PVS1

This frameshift variant in exon 7, of 9, results in a premature stop codon in exon 8, which is predicted to cause NMD (PVS1).

PS3

Expression vectors containing Foxn1 variants were transfected into HeLa cells along with the β5t-luciferase reporter construct, a well-defined transcriptional target of Foxn1. This variant resulted in 0.90% activity in the reporter assay compared to WT (PMID: 37419334). This evidence is not considered here since this variant was used as a Pathogenic control for this assay.

PS4

One heterozygous case has been reported (SCV001579576.3) with a consistent phenotype 0.25pt (PS4_NotMet).

PM3

Pt1 is compound heterozygous with c.1089_1103del which has not yet been classified by the SCID VCEP (PMID: 31566583).

Curation History

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