Submissions for variant NM_000552.5(VWF):c.7390C>T (p.Arg2464Cys)

gnomAD frequency: 0.00014  dbSNP: rs61751286

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000086880	SCV000521090	likely pathogenic	not provided	2024-08-28	criteria provided, single submitter	clinical testing	Published laboratory and functional studies demonstrate that R2464C is associated with an abnormal fast-running and smeary VWF multimer profile (PMID: 19566550, 18315556); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30504698, 18230755, 18315556, 19506359, 19506353, 23216583, 19566550, 17200787, 16985174, 17190853, 31589614, 34272389, 32108991, 31968368, 38203291, 33556167, 27535533, 37647632)
Illumina Laboratory Services, Illumina	RCV000778374	SCV000914593	pathogenic	Hereditary von Willebrand disease	2018-08-14	criteria provided, single submitter	clinical testing	The VWF c.7390C>T (p.Arg2464Cys) missense variant has been reported in six patients with type 1 von Willebrand disease (VWD), including in four in a heterozygous state, in one in a compound heterozygous state, and in one in a heterozygous state where the patient carried another missense variant but phase was not determined (Goodeve et al. 2007; James et al. 2007). At least two unrelated patients who were heterozygous for the p.Arg2464Cys variant each had two additional affected family members who carried the variant, while the compound heterozygote had three affected family members who carried the p.Arg2464Cys variant, though the authors did not state whether these individuals also carried the second missense variant; none of the unaffected members of these families carried the p.Arg2464Cys variant (Goodeve et al. 2007; Eikenboom et al. 2009). Control data are unavailable for this variant, which is reported at a frequency of 0.000167 in the African population from the Genome Aggregation Database. Following multimer profile assessment, three patients carrying the p.Arg2464Cys variant were shown to have abnormal multimers present (Goodeve et al. 2007). Transfection of COS-7 cells with the p.Arg2464Cys variant alone demonstrated secretion of all VWF multimers, but with an abnormal anodic migration (Eikenboom et al. 2009). Based on the collective evidence, the p.Arg2464Cys variant is classified as pathogenic for von Willebrand disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000086880	SCV001134920	likely pathogenic	not provided	2023-02-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00013 (17/128840 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, this variant has been reported in individuals with type 1 von Willebrand disease (VWD) (PMIDs: 34272389 (2021), 33556167 (2021), 31249928 (2018), 16985174 (2007) and 17190853 (2007)). Functional studies have shown that this variant results in a mild reduction of secreted VWF and an abnormal fast-running and smeary VWF multimer profile (PMIDs: 17200787 (2007), 16985174 (2007), 18315556 (2008), and 19566550 (2009)). 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. Based on the available information, this variant is classified as likely pathogenic.
Revvity Omics, Revvity	RCV000086880	SCV002024800	likely pathogenic	not provided	2021-01-15	criteria provided, single submitter	clinical testing
Laboratory of Hematology, Radboud University Medical Center	RCV002264670	SCV002546249	pathogenic	von Willebrand disease type 1	2020-12-10	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782236	SCV002572291	likely pathogenic	von Willebrand disorder	2024-09-10	criteria provided, single submitter	clinical testing	Variant summary: VWF c.7390C>T (p.Arg2464Cys) results in a non-conservative amino acid change located in the VWFC domain (IPR001007) 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 8e-05 in 251310 control chromosomes. 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.7390C>T has been reported in the literature in heterozygous and compound heterozygous individuals affected with Von Willebrand Disease (Goodeve_2006, James_2007, Castaman_2008, Manderstedt_2018, Almazni_2020, Baz_2021). These data indicate that the variant is likely to be associated with disease. At least one functional study reports this variant in transfected cells showed a mild reduction in the amount of secreted VWF and characteristic faster running multimeric bands indicating that this mutation is probably causative(Eikenboom_2009). The following publications have been ascertained in the context of this evaluation (PMID: 32935436, 34272389, 18230755, 19566550, 16985174, 17190853, 31249928, 26986123, 18230755). ClinVar contains an entry for this variant (Variation ID: 100467). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genetics and Molecular Pathology, SA Pathology	RCV002264670	SCV004175472	likely pathogenic	von Willebrand disease type 1	2021-09-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000086880	SCV004565162	likely pathogenic	not provided	2023-11-09	criteria provided, single submitter	clinical testing	The VWF c.7390C>T; p.Arg2464Cys variant (rs61751286) is reported in individuals diagnosed with type 1 VWD or unclassified VWD and has been reported to segregate with disease in families (Eikenboom 2009, Goodeve 2007, Lester 2007, Manderstedt 2018, Sadler 2021). This variant is also reported in ClinVar (Variation ID: 100467). It is observed in the general population with an overall allele frequency of 0.008% (23/282494 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.397). Based on available information, this variant is considered to be likely pathogenic. References: Eikenboom J et al. Expression of 14 von Willebrand factor mutations identified in patients with type 1 von Willebrand disease from the MCMDM-1VWD study. J Thromb Haemost. 2009 Aug;7(8):1304-12. PMID: 19566550. 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. Lester WA et al. The R2464C missense mutation in the von Willebrand factor gene causes a novel abnormality of multimer electrophoretic mobility and falls into the subgroup of type 2 von Willebrand disease 'unclassified'. Thromb Haemost. 2007 Jan;97(1):159-60. PMID: 17200787. Manderstedt E et al. Genetic Variation in the von Willebrand Factor Gene in Swedish von Willebrand Disease Patients. TH Open. 2018 Jan 30;2(1):e39-e48. PMID: 31249928. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002264670	SCV005398995	pathogenic	von Willebrand disease type 1	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative, loss of function, and gain of function are known mechanisms of disease in this gene and are associated with von Willebrand disease (VWD), type 1 (MIM#193400), type 2 (MIM#613554), and type 3 (MIM#277480) (PMID: 19372260, 30488424, 11698279). (I) 0108 - This gene is associated with both recessive and dominant disease. VWD types 1, 2A, 2B, and 2M are inherited in an autosomal dominant pattern, while types 2N and 3 are inherited in an autosomal recessive pattern (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. VWD type 1 has been noted to have reduced penetrance (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (23 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2; highest allele frequency: 12 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated von Willebrand factor type C domain (Pfam). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times in the ClinVar database and the literature in individuals with von Willebrand disease type 1, typically in the heterozygous state (PMID: 16985174, 17190853, 31249928). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro studies on this variant indicate that it causes a multimerisation defect (PMID: 19566550, 18315556). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005364983	SCV005921265	likely pathogenic	von Willebrand disease type 1; von Willebrand disease type 3	2022-04-05	criteria provided, single submitter	research
Academic Unit of Haematology, University of Sheffield	RCV000086880	SCV000119086	not provided	not provided		no assertion provided	not provided
Birmingham Platelet Group; University of Birmingham	RCV001270490	SCV001450789	pathogenic	Abnormal bleeding; Thrombocytopenia	2020-05-01	no assertion criteria provided	research