X-154957060-C-T
Variant summary
Our verdict is Pathogenic. Variant got 8 ACMG points: 8P and 0B. PP4_ModeratePP3PM2_SupportingPS4
This summary comes from the ClinGen Evidence Repository: The c.1649G>A (p.Arg550His) variant is absent from males in gnomAD v2.1.1. It is reported in heterozygotes at a frequency of 0.00002442 (2/81904 alleles) in the non-Finnish European population. At least 35 male individuals with mild hemophilia A are found in the literature and internal laboratory data with the Arg550His variant. More cases are available in the literature (EAHAD reports 64 patients), however >8 probands have been counted towards PS4_VeryStrong and one for PP4_moderate. This variant is associated with discrepant factor VIII activity levels with some individuals having normal levels on one-stage assays and levels in the mild hemophilia range on a chromogenic, or two-stage, assay (CDC Champs/EAHAD databases). Some individuals have been reported to have a history of inhibitor formation to factor replacement products (CDC Champs/EAHAD databases). The c.1649G>A (p.Arg550His) missense variant has a REVEL score of 0.78 (>0.6). Other variants at the same residue, Arg550Cys, Arg550Gly, Arg550Leu and Arg550Pro have been reported, but evidence from these variant curations has not been used in classifying the Arg550His variant. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_VeryStrong, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA255115/MONDO:0010602/071
Frequency
Consequence
NM_000132.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
F8 | ENST00000360256.9 | c.1649G>A | p.Arg550His | missense_variant | 11/26 | 1 | NM_000132.4 | ENSP00000353393.4 | ||
F8 | ENST00000647125.1 | n.*1525G>A | non_coding_transcript_exon_variant | 12/14 | ENSP00000496062.1 | |||||
F8 | ENST00000647125.1 | n.*1525G>A | 3_prime_UTR_variant | 12/14 | ENSP00000496062.1 |
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD3 exomes AF: 0.0000109 AC: 2AN: 183443Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67891
GnomAD4 exome AF: 0.00000183 AC: 2AN: 1095586Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 1AN XY: 361004
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Hereditary factor VIII deficiency disease Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 30, 2024 | Variant summary: F8 c.1649G>A (p.Arg550His) results in a non-conservative amino acid change located in the Multicopper oxidase-like, N-terminal domain (IPR011707) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 183443 control chromosomes (gnomAD). c.1649G>A has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A; e.g. Gilmore_2010). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in substantially reduced F8 activity (Pipe_2001). The following publications have been ascertained in the context of this evaluation (PMID: 20148980, 11157485). ClinVar contains an entry for this variant (Variation ID: 10225). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1995 | - - |
Pathogenic, reviewed by expert panel | curation | ClinGen Coagulation Factor Deficiency Variant Curation Expert Panel, Clingen | Feb 02, 2024 | The c.1649G>A (p.Arg550His) variant is absent from males in gnomAD v2.1.1. It is reported in heterozygotes at a frequency of 0.00002442 (2/81904 alleles) in the non-Finnish European population. At least 35 male individuals with mild hemophilia A are found in the literature and internal laboratory data with the Arg550His variant. More cases are available in the literature (EAHAD reports 64 patients), however >8 probands have been counted towards PS4_VeryStrong and one for PP4_moderate. This variant is associated with discrepant factor VIII activity levels with some individuals having normal levels on one-stage assays and levels in the mild hemophilia range on a chromogenic, or two-stage, assay (CDC Champs/EAHAD databases). Some individuals have been reported to have a history of inhibitor formation to factor replacement products (CDC Champs/EAHAD databases). The c.1649G>A (p.Arg550His) missense variant has a REVEL score of 0.78 (>0.6). Other variants at the same residue, Arg550Cys, Arg550Gly, Arg550Leu and Arg550Pro have been reported, but evidence from these variant curations has not been used in classifying the Arg550His variant. In summary, this variant meets criteria to be classified as pathogenic. ACMG/AMP criteria applied, as specified by the Coagulation Factor Deficiency Variant Curation Expert Panel for F8: PS4_VeryStrong, PP3, PM2_Supporting. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Mar 05, 2021 | - - |
Hereditary factor VIII deficiency disease;C5676879:Thrombophilia, X-linked, due to factor 8 defect Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 30, 2024 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 19, 2023 | The F8 c.1649G>A; p.Arg550His variant, also known as p.Arg531His, is reported in the literature in multiple individuals affected with mild hemophilia A (Markoff 2009, Schwaab 1995, Winter 2008, Factor VIII database and references therein). This variant is reported in ClinVar (Variation ID: 10225), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (Cys, Gly, Leu, Pro) have been reported in individuals with mild to moderate hemophilia A and are considered pathogenic (Factor VIII database and references therein). Functional characterization of the p.Arg550His variant protein indicates an increase in dissociation from the thrombin-activated heterodimer (Pipe 2001). Computational analyses predict that this variant is deleterious (REVEL: 0.738). Based on available information, the p.Arg550His variant is considered to be mildly pathogenic. References: Link to Factor VIII database: http://www.factorviii-db.org/ Markoff A et al. Combined homology modelling and evolutionary significance evaluation of missense mutations in blood clotting factor VIII to highlight aspects of structure and function. Haemophilia. 2009 15(4):932-41. PMID: 19473423. Pipe S et al. Hemophilia A mutations associated with 1-stage/2-stage activity discrepancy disrupt protein-protein interactions within the triplicated A domains of thrombin-activated factor VIIIa. Blood. 2001 97(3):685-91. PMID: 11157485. Schwaab R et al. Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs. Br J Haematol. 1995 91(2):458-64. PMID: 8547094. Winter P et al. A recurrent F8 mutation in Irish haemophilia A patients: evidence for a founder effect. Haemophilia. 2008 14(2):394-5. PMID: 18179574. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at