rs61750603
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBS2_Supporting
The NM_000552.5(VWF):c.5191T>A(p.Ser1731Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,614,210 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000552.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000992 AC: 151AN: 152198Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.00157 AC: 394AN: 251490Hom.: 1 AF XY: 0.00162 AC XY: 220AN XY: 135920
GnomAD4 exome AF: 0.00118 AC: 1719AN: 1461894Hom.: 3 Cov.: 32 AF XY: 0.00122 AC XY: 887AN XY: 727248
GnomAD4 genome AF: 0.000991 AC: 151AN: 152316Hom.: 2 Cov.: 32 AF XY: 0.000886 AC XY: 66AN XY: 74492
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:2Benign:1Other:1
The VWF c.5191T>A (p.Ser1731Thr) variant has been reported in the published literature in individuals with Type 2M von Willebrand disease (PMID: 26986123 (2016), 28971901 (2017), 34758185 (2022)) and in individuals with bleeding symptoms as well as in two asymptomatic siblings (PMID: 19687512 (2009)). This variant has also been reported in a homozygous state in an individual with Glanzmann thrombasthenia (GT) (PMID: 30792900 (2019)). Published functional studies showed that this variant caused decreased platelet adhesion due to defective binding to type I and type III collagen (PMID: 11583318 (2001), 19687512 (2009), 20345715 (2010), 29604837 (2018)) while one study showed a minimal effect on Type III collagen binding (PMID: 25051961 (2014)). The frequency of this variant in the general population, 0.021 (217/10370 chromosomes in Ashkenazi Jewish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on VWF mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant. -
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The p.Ser1731Thr variant in VWF has been reported in at least 3 individuals with clinical features of Von Willebrand disease and 1 homozygous individual with Glanzmann thrombasthenia, and segregated with disease in 2 affected relatives from 2 families. However, it was also identified in 1 individual with an alternate molecular cause of disease and 4 asymptomatic relatives (Ribba 2001 PMID: 11583318, Riddell 2009 PMID: 19687512, Veyradier 2016 PMID: 26986123, Owaidah 2019 PMID: 30792900, Al-Doory 2020). This variant has been identified in 2.1% (217/10370) of Ashkenazi Jewish chromosomes and 0.11% (136/129190) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and is reported in ClinVar (Variation ID: 100420). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that the p.Ser1731Thr variant may have a partial impact to protein function (Flood 2009 PMID: 20345715, Riddell 2009 PMID: 19687512, Flood 2015 PMID: 25662333); however, these in vitro results may not be biologically relevant. In summary, while the clinical significance of this variant is uncertain, its frequency suggests that it is more likely to be benign. ACMG/AMP Criteria applied: PS3_Supporting, BS1. -
Published functional studies including in vitro collagen binding assays showed a reduction in binding to both type I and type III collagen (PMID: 20345715, 25051961); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21967679, 25662333, 25051961, 19506356, 19687512, 26986123, 16870550, 30046704, 31605304, 32394456, 24385719, 23406206, 18036186, 23216583, 32998182, 19630771, 34426522, 30792900, 29924855, 34758185, 34708896, 37163579, 20345715, 11583318, 38762018, 38968155) -
VWF: PS3:Supporting, BS1 -
not specified Uncertain:3
Variant summary: VWF c.5191T>A (p.Ser1731Thr) results in a conservative amino acid change located in the third VWF type A (A3) domain (IPR002035), which is the main binding site for collagens type I and III (UniProt) 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 0.0012 in 1614210 control chromosomes in the gnomAD database, including 5 homozygotes. However, in certain subpopulations, e.g. in the Ashkenazi Jewish the variant was found at a much higher allele frequency. The observed relatively high frequency, together with the homozygous occurrences, might indicate a benign nature for the variant, or alternatively the variant might represent a hypomorphic allele associated with a milder phenotype / reduced penetrance.The variant, c.5191T>A, has been reported in the literature in multiple heterozygous individuals affected with Von Willebrand Disease (e.g. Ribba_2001, Riddell_2009, Veyradier_2016, Borras_2017, Maas_2022), and in a homozygous individual with Glanzmann thrombasthenia (Owaidah 2019). However, in at least one family the variant was also observed in asymptomatic younger family members (Riddell_2009), although they also displayed the biochemical phenotype (i.e. decresed VWF binding to type I collagen; see below). Furthermore, in one of these reported cases a co-occurring pathogenic variant could explain the phenotype (Borras_2017). Several publications reported experimental evidence evaluating an impact on protein function, and in general demonstrated reduced binding to collagen type I, with mostly unaffected binding to collagen type III (e.g. Ribba_2001, Riddell_2009, Flood_2010, Shida_2014, Posch_2018). This finding was confirmed by utilizing a knock-in mouse model (Shida_2014), however authors of the study concluded that mice were still able to initiate platelet adhesion and thrombus formation in their model, demonstrating an important role for collagen-independent pathway(s) of primary hemostasis that likely contribute to the mild bleeding phenotype in patients with VWF collagen-binding mutations. The following publications have been ascertained in the context of this evaluation (PMID: 11583318, 19687512, 26986123, 28971901, 30792900, 20345715, 25051961, 29604837, 34758185, 34708896). ClinVar contains an entry for this variant (Variation ID: 100420). Based on the evidence outlined above, the variant was classified as uncertain significance. -
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DNA sequence analysis of the VWF gene demonstrated a sequence change, c.5191T>A, in exon 30 that results in an amino acid change, p.Ser1731Thr. This sequence change has been described in the gnomAD database with a frequency of 2.1% in Ashkenazi Jewish subpopulation (dbSNP rs61750603). This sequence change has been previously described in the heterozygous states in individuals and families with von Willebrand disease (PMIDs: 11583318, 26986123, 19687512, 28971901). The p.Ser1731Thr change affects a highly conserved amino acid residue located in the A3 domain of the VWF protein. Functional studies show p.Ser1731Thr disrupts the binding of VWF to collagen (PMIDs: 11583318, 19687512, 20345715). Due to the lack of sufficient evidence, the clinical significance of the p.Ser1731Thr change remains unknown at this time. -
VWF-related disorder Pathogenic:1
The VWF c.5191T>A variant is predicted to result in the amino acid substitution p.Ser1731Thr. This variant has been reported previously to reduce binding between VWF protein and different collagen types (including collagen I and III) and has been reported, with variable expressivity, in several patients with von Willebrand Disease (Ribba et al. 2001. PubMed ID: 11583318; Flood et al. 2010. PubMed ID: 20345715; Riddell et al. 2009. PubMed ID: 19687512; Veyradier et al. 2016. PubMed ID: 26986123, see figure 6). However, several unaffected family members, who displayed only mildly altered biochemical findings, also harbored this variant, suggesting incomplete penetrance (see, for example, Riddell et al. 2009. PubMed ID: 19687512). This variant was also reported in the homozygous state in an individual with suspected Glanzmann thrombasthenia (Owaidah et al. 2019. PubMed ID: 30792900). This variant is reported in 2.1% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. A different missense change impacting the same amino acid (p.Ser1731Leu) was reported in two siblings with significantly reduced values for von Willebrand factor collagen-binding activity (Fels et al. 2022. PubMed ID: 35104900). Taken together, the VWF c.5191T>A (p.Ser1731Thr) variant is interpreted as likely pathogenic with reduced penetrance and variable expressivity. -
Hereditary von Willebrand disease Uncertain:1
The c.5191T>A (p.Ser1731Thr) variant has been reported in three studies in which it is found in at least four patients in a heterozygous state (Ribba et al. 2001, Riddell et al. 2009, Veyradier et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00205 in the European (Non-Finnish) population from the Exome Sequencing Project. This frequency is high in comparison to disease prevalence, but may be explained by a milder phenotype or reduced penetrance. Functional studies including expression of the variant in COS-7 cells demonstrated significantly decreased binding of the variant protein to collagen. Analysis in HEK293T cells showed the p.Ser1731Thr variant affects binding to collagen type I but not type III. Additional functional studies utilizing mouse models, HEK293T cell constructs, flow chamber analysis, and collagen thin films in flow assays support normal expression but reduced collagen binding of the p.Ser1731Thr variant (Flood et al. 2010; Shida et al. 2014; Hansen et al. 2011). Based on the limited number of cases but with supporting functional data, the p.Ser1731Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for von Willebrand disease. -
von Willebrand disease type 2 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at