Submissions for variant NM_001369369.1(FOXN1):c.1201_1216del (p.Pro401fs)

dbSNP: rs1064793129

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000555732	SCV005382654	pathogenic	T-cell immunodeficiency, congenital alopecia, and nail dystrophy	2024-07-29	reviewed by expert panel	curation	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.
GeneDx	RCV000480423	SCV000565018	likely pathogenic	not provided	2017-06-19	criteria provided, single submitter	clinical testing	The c.1201_1216del16 variant in the FOXN1 gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, GeneDx has observed this variant as a de novo heterozygous variant (without a second identifiable FOXN1 variant) in another individual referred for exome analysis. The c.1201_1216del16 variant causes a frameshift starting with codon Proline 401, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 144 of the new reading frame, denoted p.Pro401AlafsX144. This variant is predicted to replace the last 248 amino acids of the protein with 143 incorrect amino acids. The c.1201_1216del16 variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555732	SCV000645325	pathogenic	T-cell immunodeficiency, congenital alopecia, and nail dystrophy	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro401Alafs*144) in the FOXN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 248 amino acid(s) of the FOXN1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with FOXN1 haploinsufficiency (PMID: 31447097, 31566583; Invitae). ClinVar contains an entry for this variant (Variation ID: 418218). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects FOXN1 function (PMID: 31566583). This variant disrupts a region of the FOXN1 protein in which other variant(s) (p.Gln489Argfs*61) have been determined to be pathogenic (PMID: 31566583). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV001027396	SCV001189943	pathogenic	T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant	2020-11-11	no assertion criteria provided	literature only