rs61749404
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP2PP3BS2_Supporting
The NM_000552.5(VWF):c.4024C>T(p.Arg1342Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000057 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000552.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000116 AC: 29AN: 250684Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135612
GnomAD4 exome AF: 0.0000472 AC: 69AN: 1461628Hom.: 0 Cov.: 38 AF XY: 0.0000413 AC XY: 30AN XY: 727130
GnomAD4 genome AF: 0.000151 AC: 23AN: 152322Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9AN XY: 74496
ClinVar
Submissions by phenotype
not provided Uncertain:2Other:1
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The VWF c.4024C>T (p.Arg1342Cys) variant (also known as R1342C) has been reported in the published literature in individuals/families with Type 1 (PMID: 19453940 (2010)) or Type 2 von Willebrand disease (vWD) (PMIDs: 27443694 (2016), 19506361 (2009), 19298374 (2009), 18315556 (2008), 16985174 (2007), and 16321553 (2006)). In addition, this variant has been reported in healthy control individuals (PMIDs: 33556167 (2021) and 22197721 (2012)). The frequency of this variant in the general population, 0.0008 (20/24896 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools (i.e., MutationTaster and PolyPhen-2) for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Please note that these prediction tools are not fully validated, and therefore, should be viewed with caution. Based on the available information, we are unable to determine the clinical significance of this variant. -
The VWF c.4024C>T; p.Arg1342Cys variant (rs61749404) is reported in the literature in individuals affected with von Willebrand disease type 1 (Goodeve 2007), but has also been found in healthy controls (Bellissimo 2012, Sadler 2021). This variant is reported in ClinVar (Variation ID: 100616) and is found in the African/African-American population with an allele frequency of 0.08% (20/24,896 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.907). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Bellissimo DB et al. VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. Blood. 2012 Mar 1;119(9):2135-40. PMID: 22197721. Goodeve A et al. Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). Blood. 2007 Jan 1;109(1):112-21. PMID: 16985174. Sadler B et al. von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene. Blood. 2021 Jun 10;137(23):3277-3283. PMID: 33556167. -
not specified Uncertain:1
Variant summary: VWF c.4024C>T (p.Arg1342Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 250684 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in VWF causing Von Willebrand Disease, allowing no conclusion about variant significance. c.4024C>T has been reported in the literature in individuals affected with Von Willebrand Disease without strong evidence of causality (e.g. Kakela_2006, Goodeve_2007). 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: 16985174, 16321553, 19298374). ClinVar contains an entry for this variant (Variation ID: 100616). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at