The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_001369369.1(FOXN1):c.1201_1216del (p.Pro401fs)

CA16620352

418218 (ClinVar)

Gene: FOXN1
Condition: T-cell immunodeficiency, congenital alopecia, and nail dystrophy
Inheritance Mode: Semidominant inheritance
UUID: cdf82ba5-1671-4aa3-9bd9-1463be074b0f
Approved on: 2024-07-29
Published on: 2024-07-29

HGVS expressions

NM_001369369.1:c.1201_1216del
NM_001369369.1(FOXN1):c.1201_1216del (p.Pro401fs)
NC_000017.11:g.28534772_28534787del
CM000679.2:g.28534772_28534787del
NC_000017.10:g.26861790_26861805del
CM000679.1:g.26861790_26861805del
NC_000017.9:g.23885917_23885932del
NG_007260.1:g.15832_15847del
ENST00000577936.2:c.1201_1216del
ENST00000579795.6:c.1201_1216del
ENST00000226247.2:c.1201_1216del
ENST00000481916.6:c.*1195+69277_*1195+69292del
ENST00000579795.5:c.1201_1216del
NM_003593.2:c.1201_1216del
NM_003593.3:c.1201_1216del
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Pathogenic

Met criteria codes 4
PS4 PP4 PVS1_Strong PM2_Supporting
Not Met criteria codes 2
PS3 PP1

Evidence Links 0

Expert Panel

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.1201_1216del (p.Pro401AlafsTer?) frameshift variant in exon 8 results in a premature stop codon in the final exon (exon 9) at codon 544. 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). This variant is absent from gnomADv2.1.1 (PM2_supporting). This variant has been reported heterozygous in at least 10 patients (PS4) with T lymphopenia, particularly low CD8+ cell counts, at least one of whom also had nail dystrophy (P13 of PMID: 31447097; 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_strong, PM2_supporting, PS4 and PP4 as specified by the ClinGen SCID VCEP FOXN1 subgroup.
Met criteria codes
PS4
An additional nine patients (P9-P12 PMID: 31447097 and P10-P14PMID: 31566583) have been reported with this variant. Each patient had low CD3 cells (73-930; 0.25pt) and low CD8 cells (0-142; 0.25pt). The variant was identified by "DNA sequencing and targeted analysis of SCID-associated genes" or exome sequencing (0.5pt) 1pt x 9 patients = 9pts
PP4
P13 (PMID: 31447097) had low TREC levels, and cell counts (cells/µL): CD3 538 [nv:2500-5500], CD4 782 [nv:1660-4000], CD8 81 [nv:560-1700] (low for age 0.25pt), CD19 824 [nv:300-2000], CD16/CD56 398 [nv:170-1100], nail dystrophy (0.25pt). The variant was identified by "DNA sequencing and targeted analysis of SCID-associated genes" (0.5pt)
PVS1_Strong
This frameshift variant in exon 8 results in a premature stop codon in the final exon (exon 9) at codon 544. 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).
PM2_Supporting
This variant is absent from gnomADv4.0 (PM2_supporting).
Not Met criteria codes
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 1.4% 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.
PP1
P26 and P29 (PMID: 31447097) are each a parent of one of patients of P9-P13 (not clear which parent belongs to which patient). Both parents are also heterozygous for c.1201_1216del16 however T lymphopenia, congenital alopecia, and/or nail dystrophy were not mentioned for the parents so they are not considered for segregation analysis.
Curation History
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