Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_001369369.1(FOXN1):c.1288C>T (p.Pro430Ser)

CA8459494

322430 (ClinVar)

Gene: FOXN1
Condition: T-cell immunodeficiency, congenital alopecia, and nail dystrophy
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 5acb125e-41f9-41b3-9625-2a6f8ced798f
Approved on: 2024-07-29
Published on: 2024-07-29

HGVS expressions

NM_001369369.1:c.1288C>T
NM_001369369.1(FOXN1):c.1288C>T (p.Pro430Ser)
NC_000017.11:g.28534859C>T
CM000679.2:g.28534859C>T
NC_000017.10:g.26861877C>T
CM000679.1:g.26861877C>T
NC_000017.9:g.23886004C>T
NG_007260.1:g.15919C>T
ENST00000577936.2:c.1288C>T
ENST00000579795.6:c.1288C>T
ENST00000226247.2:c.1288C>T
ENST00000481916.6:c.*1195+69192G>A
ENST00000579795.5:c.1288C>T
NM_003593.2:c.1288C>T
NM_003593.3:c.1288C>T
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Benign

Met criteria codes 2
BP4 BA1
Not Met criteria codes 4
BS4 BS3 BP2 PP4

Evidence Links 2

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.1288C>T (p.Pro430Ser) missense variant has a gnomAD popmax filtering allele frequency of 0.04634 based on 6036/128650 alleles in the European (non-Finnish) population, which is greater than >0.00447 and thus meets BA1. The variant has a REVEL score of 0.168, which is less than 0.290 and thus meets criteria for BP4, suggesting no effect on gene function. Of note, this variant has been reported (PMID: 31566583) in the context of T cell immunodeficiency, however it was in trans with c.1465del which is considered to be the causal variant. Pro430Ser is not considered to contribute to the phenotype, which is consistent with functional studies of the variant which found the variant had no significant effect on expression or Luciferase activity compared to WT (PMID: 31566583) and a heterozygous mouse model was unaffected (PMID: 37419334). In summary this variant meets criteria to be classified as benign for semidominant T-cell immunodeficiency, congenital alopecia, and nail dystrophy based on the ACMG/AMP criteria, as specified by the ClinGen SCID VCEP: BA1, BP4.
Met criteria codes
BP4
The variant has a REVEL score of 0.168, which is less than 0.290 and thus meets criteria for BP4, suggesting no effect on gene function. Additionally, no splicing effect is predicted by SpliceAI (delta score <=0.01).
BA1
The variant has a gnomAD Grpmax filtering allele frequency of 0.05020 based on 59628/1179920 alleles in the European (non-Finnish) population, which is greater than >0.00447 and thus meets BA1. Note the Finnish population has an even higher MAF of 0.07151.
Not Met criteria codes
BS4
This variant was inherited from the mother, who was not noted to be affected, however specific evaluation of the mother was not reported (PMID: 31566583).
BS3
To determine how the variant affects the expression and function of the protein, it was introduced into the cDNA of murine Foxn1 and the authors performed protein expression and promoter-based reporter assay comparisons. The Pro430Ser variant had no significant effect on expression or Luciferase activity, which was 100% of WT levels (PMID: 31566583). Furthermore, e16.5 thymuses were obtained from Foxn1 wild-type (Wt) or variant embryos heterozygous for Pro430Ser. The number and percentage of the different cell subsets in the tissues were determined by cell counting and flow-cytometric analyses following cell surface staining with mAbs detecting CD4, CD8, EpCam (TECs), and CD45 (hematopoietic cells). No statistically significant differences were found between WT and Pro430Ser mice (PMID: 37419334). BS3 is not applied per VCEP specifications.
To determine how the variant affects the expression and function of the protein, it was introduced into the cDNA of murine Foxn1 and the authors performed protein expression and promoter-based reporter assay comparisons. The Pro430Ser variant had no significant effect on expression or Luciferase activity, which was 100% of WT levels (PMID: 31566583). PubMed:31566583
e16.5 thymuses were obtained from Foxn1 wild-type (Wt) or variant embryos heterozygous for Pro430Ser. The number and percentage of the different cell subsets in the tissues were determined by cell counting and flow-cytometric analyses following cell surface staining with mAbs detecting CD4, CD8, EpCam (TECs), and CD45 (hematopoietic cells). No statistically significant differences were found between WT and Pro430Ser mice. PubMed:37419334
BP2
Exome sequencing, with Sanger confirmation, found the Pro430Ser variant inherited from the mother and a de novo c.1465delC variant on the other allele (PMID: 31566583). This is not considered for the BP2 criteria because only pathogenic variants in cis are considered.
PP4
PMID: 31566583 reports a patient with this variant, they have T–/loB+NK+ leaky SCID phenotype with persistent severe T cell lymphopenia, absent thymopoiesis, and diminished T cell function. Patient not considered because variant meets BA1
Curation History
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