ClinVar Miner

Submissions for variant NM_001369369.1(FOXN1):c.763C>T (p.Arg255Ter)

gnomAD frequency: 0.00001  dbSNP: rs104894562
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen RCV000009300 SCV005382685 pathogenic T-cell immunodeficiency, congenital alopecia, and nail dystrophy 2024-07-29 reviewed by expert panel curation The NM_001369369.1(FOXN1):c.763C>T (p.Arg255Ter) nonsense variant occurs in exon 5 of 9 and is predicted to result in non-sense mediated decay (PVS1). The highest MAF in gnomAD v2.1.1 is 0.000008790 (1/113762 alleles) in the European (non-Finnish) population. This is below the SCID VCEP specified threshold of <0.00002412 (PM2_supporting). At least one patient (PMID: 10206641) is described with congenital alopecia, nail dystrophy, and very low T cell number which is highly specific to FOXN1 deficiency (PP4). This individual had an affected siblings, also homozygous for the variant, as reported in PMID: 10206641. Additionally PMID: 31447097 reports another 14 heterozygous relatives with nail dystrophy belonging to same extended family (estimated LOD score 4.82; PP1_Strong). At least two additional unrelated patients have been reported, these three unrelated patients are all homozygous (PMIDs: 28636882, 20978268, 10206641; PM3). 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, PP4, PP1_strong, PM3 as specified by the ClinGen SCID VCEP FOXN1 subgroup (specifications v1.0).
Labcorp Genetics (formerly Invitae), Labcorp RCV000009300 SCV001230583 pathogenic T-cell immunodeficiency, congenital alopecia, and nail dystrophy 2023-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg255*) in the FOXN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FOXN1 are known to be pathogenic (PMID: 10206641, 15180707, 31447097). This variant is present in population databases (rs104894562, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with severe combined immunodeficiency, alopecia, and nail dystrophy (PMID: 10206641, 15180707, 20864124, 20978268, 21507891, 28636882). It is commonly reported in individuals of Italian ancestry (PMID: 15180707). ClinVar contains an entry for this variant (Variation ID: 8757). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000009300 SCV000029518 pathogenic T-cell immunodeficiency, congenital alopecia, and nail dystrophy 2011-06-01 no assertion criteria provided literature only
OMIM RCV001027389 SCV001189936 pathogenic T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant 2011-06-01 no assertion criteria provided literature only

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