Submissions for variant NM_000132.4(F8):c.1636C>T (p.Arg546Trp)

dbSNP: rs137852416

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003103711	SCV000883824	pathogenic	not provided	2024-09-06	criteria provided, single submitter	clinical testing	The F8 c.1636C>T; p.Arg546Trp variant (rs137852416), also known as Arg527Trp, is reported in the literature in individuals with mild to moderate hemophilia A (Bogdanova 2007, Schwaab 1995, Factor VIII database and references therein). This variant is reported in more than 80 affected individuals in the Factor VIII database with clotting activity measurements ranging from 2.3% to 42% of normal. This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 546 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.837). Based on available information, this variant is considered to be pathogenic. References: Factor VIII database: http://f8-db.eahad.org Bogdanova N et al. Spectrum of molecular defects and mutation detection rate in patients with mild and moderate hemophilia A. Hum Mutat. 2007 Jan;28(1):54-60. Schwaab R et al. Characterization of mutations within the factor VIII gene of 73 unrelated mild and moderate haemophiliacs. Br J Haematol. 1995 Oct;91(2):458-64.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852048	SCV000899541	pathogenic	Hereditary factor IX deficiency disease	2019-02-01	criteria provided, single submitter	research
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000010935	SCV002512663	likely pathogenic	Hereditary factor VIII deficiency disease	2021-12-04	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 strong, PM2 moderate, PP3 supporting, PP4 supporting
Baylor Genetics	RCV000010935	SCV003835971	pathogenic	Hereditary factor VIII deficiency disease	2021-02-09	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000010935	SCV003841361	likely pathogenic	Hereditary factor VIII deficiency disease	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000010222 / PMID: 1924291). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV003103711	SCV005201773	pathogenic	not provided	2024-01-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R527W); This variant is associated with the following publications: (PMID: 18691168, 9439662, 34889362, 30997536, 1924291, 32224444, 7728145, 19473423, 31064749, 8547094, 7794769, 25212677, 34708896, 9886318, 11857744, 10404764, 8449505, 9029040, 11748850, 12871415, 16972227, 24452774, 16128892, 16769589, 17445092, 18540892, 34275734, 18565236)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000010935	SCV005203713	pathogenic	Hereditary factor VIII deficiency disease	2024-07-03	criteria provided, single submitter	clinical testing	Variant summary: F8 c.1636C>T (p.Arg546Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183428 control chromosomes (gnomAD). c.1636C>T has been reported in the literature in multiple individuals affected with Factor VIII Deficiency (Hemophilia A; e.g. Silva Pinto_2012, Rosset_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21645180, 23711237). ClinVar contains an entry for this variant (Variation ID: 10222). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000010935	SCV000031162	pathogenic	Hereditary factor VIII deficiency disease	1995-01-01	no assertion criteria provided	literature only