Submissions for variant NM_001369369.1(FOXN1):c.1364_1367del (p.Tyr455fs)

dbSNP: rs2151499024

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV001859402	SCV005382655	likely pathogenic	T-cell immunodeficiency, congenital alopecia, and nail dystrophy	2024-07-29	reviewed by expert panel	curation	NM_001369369.1(FOXN1):c.1364_1367del (p.Tyr455CysfsTer?) is a frameshift variant in exon 8 which results in a premature stop codon in the final exon (exon 9) at codon 548. 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). It has been reported in one patient and functional analysis was performed in a luciferase reporter construct, which was cotransfected into heterologous cells with an expression vector containing mutant or wild-type FOXN1. This variant had 1.6% luciferase activity compared to wild-type (PMID: 37419334; PS3_Moderate). 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: PVS1_Strong, PS3_Moderate and PM2_Supporting as specified by the ClinGen SCID VCEP FOXN1 subgroup.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001564041	SCV001787133	likely pathogenic	T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant	2021-04-19	criteria provided, single submitter	research	ACMG codes: PVS1; PM2
Revvity Omics, Revvity	RCV001780407	SCV002025163	likely pathogenic	not provided	2021-03-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001859402	SCV002191767	pathogenic	T-cell immunodeficiency, congenital alopecia, and nail dystrophy	2024-06-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr455Cysfs*94) in the FOXN1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 194 amino acid(s) of the FOXN1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FOXN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1199408). 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.