Submissions for variant NM_001369369.1(FOXN1):c.1288C>T (p.Pro430Ser)

gnomAD frequency: 0.03097  dbSNP: rs61749867

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Severe Combined Immunodeficiency Variant Curation Expert Panel, ClinGen	RCV000380418	SCV005382680	benign	T-cell immunodeficiency, congenital alopecia, and nail dystrophy	2024-07-29	reviewed by expert panel	curation	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.
Illumina Laboratory Services, Illumina	RCV000380418	SCV000401485	benign	T-cell immunodeficiency, congenital alopecia, and nail dystrophy	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000437225	SCV000516505	benign	not specified	2016-04-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000437225	SCV000539191	benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency
Labcorp Genetics (formerly Invitae), Labcorp	RCV000380418	SCV000645327	benign	T-cell immunodeficiency, congenital alopecia, and nail dystrophy	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000437225	SCV002050944	likely benign	not specified	2021-12-10	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV004703709	SCV005212376	likely benign	not provided		criteria provided, single submitter	not provided