Submissions for variant NM_000133.4(F9):c.88G>A (p.Val30Ile)

dbSNP: rs1603263395

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen	RCV004577534	SCV005061641	likely pathogenic	Hereditary factor IX deficiency disease	2024-05-09	reviewed by expert panel	curation	The c.88G>A (NM_000133.3) variant in F9 is a missense variant predicted to cause substitution of Valine by Isoleucine at amino acid 30 (p.Val30Ile). This variant has been reported in at least 5 probands meeting the hemophilia B phenotype criteria specified by the Coagulation Factor Deficiency VCEP (PS4; PMID: 10094553, 23093250, 1680287, 11122099). This variant is absent from gnomAD v2.1.1 and v3.1.2 (PM2_Supporting). Secreted conformation-specific reporter (SCSR) assay in HEK293T cells showed decreased SCSR level at ~60% of that of the WT, indicating that this variant impacts protein function (PMID: 32766856; the study is approved by the VCEP, applicable at the Supporting strength; PS3_Supporting). The computational predictor REVEL gives a score of 0.787, which is above the threshold of 0.6, evidence that correlates with impact to F9 function. The variant is the last amino acid of exon 1. The computational splicing predictor SpliceAI gives a score of 0.96 for donor loss, predicting that the variant disrupts the donor splice site of intron 1 of F9 (PP3). In summary, this variant meets the criteria to be classified as Likely Pathogenic for X-linked recessive hemophilia B based on the ACMG/AMP criteria applied, as specified by the ClinGen Coagulation Factor Deficiency VCEP: PS4, PP3, PS3_Supporting, PM2_Supporting. (ClinGen Coagulation Factor Deficiency Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for F9 Version 1.0.0., Released 10/5/2023)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806960	SCV000946984	pathogenic	Hereditary factor IX deficiency disease; Thrombophilia, X-linked, due to factor 9 defect	2018-11-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in several individuals affected with hemophilia B (PMID: 1680287, 23093250, 11122099, 10094553). This variant is also known as c.117G>A (p.Val17Ile) in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 30 of the F9 protein (p.Val30Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant also falls at the last nucleotide of exon 1 of the F9 coding sequence, which is part of the consensus splice site for this exon.