Submissions for variant NM_000552.5(VWF):c.3692A>G (p.Asn1231Ser)

dbSNP: rs61749368

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV001787126	SCV001430083	likely pathogenic	von Willebrand disease type 3	2017-12-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824942	SCV002074540	uncertain significance	not specified	2023-11-21	criteria provided, single submitter	clinical testing	Variant summary: VWF c.3692A>G (p.Asn1231Ser) results in a conservative amino acid change located in the von Willebrand factor, VWA N-terminal domain (IPR032361) of 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 0.0014 in 242782 control chromosomes, predominantly at a frequency of 0.0099 within the South Asian subpopulation in the gnomAD database, including 5 homozygotes. This frequency is does allow conclusions about variant significance. c.3692A>G has been reported in the literature in individuals affected with Von Willebrand Disease (Type 2/ 1H or mild forms) (examples: Ahmad_2013, Van Der Berg_2014, and Borras_2017, Perez-Rodriguez_2021). These reports do not provide unequivocal conclusions about association of the variant with Von Willebrand Disease. One publication reports experimental evidence evaluating an impact on protein function. These results demonstrated normal VWF synthesis, secretion and that variant protein forms normal multimers with the authors speculating either a non-causal outcome or a mild-defect (Ahmed_2013). The following publications have been ascertained in the context of this evaluation (PMID: 23179108, 28971901, 24954083, 34494337). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV002225814	SCV002504379	likely benign	not provided	2021-06-08	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Mendelics	RCV001824942	SCV002516165	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV002280902	SCV002569260	uncertain significance	von Willebrand disease type 1		criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV003447581	SCV004175354	uncertain significance	Hereditary von Willebrand disease	2021-09-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002225814	SCV004221515	uncertain significance	not provided	2023-04-13	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0099 (299/30190 chromosomes in South Asian subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with type 1 (PMIDs: 28971901 (2017)) and type 2 von Willebrand disease (PMID: 23179108 (2013)). Characterization of the variant showed normal VWF synthesis, secretion and multimers with normal functional parameters (PMIDs: 30488424 (2019), 23179108 (2013)). Based on the available information, we are unable to determine the clinical significance of this variant.