Submissions for variant NM_000552.5(VWF):c.4457C>T (p.Ser1486Leu)

gnomAD frequency: 0.00282  dbSNP: rs149424724

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000986075	SCV001134904	likely benign	not provided	2023-02-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001816687	SCV002068279	uncertain significance	not specified	2018-12-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000986075	SCV003799444	uncertain significance	not provided	2022-04-20	criteria provided, single submitter	clinical testing	The VWF c.4457C>T, p.Ser1486Leu variant (rs149424724) is reported in the literature in an individual affected with von Willebrand disease (Freitas 2019) and has been associated with a decrease in VWF plasma levels (Johnsen 2013). This variant is also reported in ClinVar (Variation ID: 560630) and is found in the African population with an allele frequency of 0.9% (213/24258 alleles) in the Genome Aggregation Database. The serine at codon 1486 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.209). However, given the lack of clinical and functional data, the significance of the p.Ser1486Leu variant is uncertain at this time. References: Freitas SDS et al. Genetic variants of VWF gene in type 2 von Willebrand disease. Haemophilia. 2019 Mar;25(2):e78-e85. PMID: 30817071. Johnsen JM et al. Common and rare von Willebrand factor (VWF) coding variants, VWF levels, and factor VIII levels in African Americans: the NHLBI Exome Sequencing Project. Blood. 2013 Jul 25;122(4):590-7. PMID: 23690449.
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV003313787	SCV004013129	uncertain significance	von Willebrand disease type 1		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001816687	SCV004804041	likely benign	not specified	2025-02-10	criteria provided, single submitter	clinical testing	Variant summary: VWF c.4457C>T (p.Ser1486Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 1613858 control chromosomes, predominantly at a frequency of 0.0091 within the African or African-American subpopulation in the gnomAD database, including 8 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in VWF causing Von Willebrand Disease phenotype. c.4457C>T has been reported in the literaure in an individual with a diagnosis of type 2 Von Willebrand Disease, without strong evidence for causality (Freitas_2019), and it has been found to have an association with decreased levels of VWF, but no association with FVIII level in healthy African American individuals (Johnsen_2013, Pankratz_2022). These reports do not provide unequivocal conclusions about association of the variant with Von Willebrand 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: 30817071, 23690449, 35552711). ClinVar contains an entry for this variant (Variation ID: 560630). Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678771	SCV000804950	uncertain significance	Hereditary von Willebrand disease	2014-08-12	no assertion criteria provided	clinical testing