Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001027390 | SCV005382678 | pathogenic | T-cell immunodeficiency, congenital alopecia, and nail dystrophy | 2024-07-29 | reviewed by expert panel | curation | The variant NM_001369369.1(FOXN1):c.958C>T (p.Arg320Trp) has been found in at least 4 individuals with FOXN1 related T cell immunodeficiency (PMIDs: 31566583, 27484032, 31447097, 20978268) in both homozygous and heterozygous states. One individual, where genomic sequencing revealed a homozygous variant, displayed phenotypes including congenital alopecia, nail dystrophy, absent T cells, and no response to PHA. This individual underwent a thymic transplant that corrected the T cell deficiency (PP4_moderate, PM3_supporting). In addition to this individual, three other patients have been described with heterozygous variants resulting in phenotypes including low TRECs and T cell lymphopenia (PS4_supporting). Additionally, the variant is present in one allele in the African/African American population in gnomADv4.0 (1/57226 alleles, MAF 0.00001747 below the PM2 threshold of <0.00002412) (PM2_supporting). The in silico meta predictor REVEL gives a score of 0.94, predicting a deleterious effect (PP3_Moderate). The variant is located within the DNA binding forkhead domain (amino acids 270-367), (PM1). Finally, the variant when expressed into HEK293 cells showed a protein function of 2% compared to wild type in a luciferase assay. In summary this variant meets criteria to be classified as pathogenic for semidominant cell immunodeficiency, congenital alopecia, and nail dystrophy due to FOXN1 deficiency based on the ACMG/AMP criteria applied: PM1, PP3_moderate, PS4_supporting, PM2_supporting, PM3_supporting, PP4_moderate, as specified by the ClinGen SCID VCEP FOXN1 subgroup. |
| Labcorp Genetics |
RCV001027390 | SCV001502733 | uncertain significance | T-cell immunodeficiency, congenital alopecia, and nail dystrophy | 2023-07-20 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects FOXN1 function (PMID: 31566583). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FOXN1 protein function. ClinVar contains an entry for this variant (Variation ID: 827572). This missense change has been observed in individual(s) with FOXN1 deficiency (PMID: 20978268, 27484032, 31447097, 31566583). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 320 of the FOXN1 protein (p.Arg320Trp). |
| Institute of Human Genetics, |
RCV004761884 | SCV005368127 | uncertain significance | T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant | 2024-07-22 | criteria provided, single submitter | clinical testing | Criteria applied: PM1,PS4_SUP,PM2_SUP,PP3 |
| OMIM | RCV001027390 | SCV001189937 | pathogenic | T-cell immunodeficiency, congenital alopecia, and nail dystrophy | 2020-11-11 | no assertion criteria provided | literature only | |
| OMIM | RCV001027391 | SCV001189938 | pathogenic | T-CELL LYMPHOPENIA, INFANTILE, WITHOUT NAIL DYSTROPHY, AUTOSOMAL DOMINANT | 2020-11-11 | no assertion criteria provided | literature only |