Submissions for variant NM_000552.5(VWF):c.1625C>G (p.Ala542Gly)

gnomAD frequency: 0.00074  dbSNP: rs141649383

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000760113	SCV000521094	uncertain significance	not provided	2023-06-22	criteria provided, single submitter	clinical testing	Observed in the homozygous state in an individual with von Willebrand disease who had an additional homozygous VWF variant in cis (Corrales et al., 2010); Observed in individuals with von Willebrand disease who have a second VWF variant, however it is unknown if these variants are in cis or trans (Sadler et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26986123, 28971901, 31064749, 27532107, 33556167, 20801902)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000760113	SCV000889895	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with low VWF and/or Type 1 von Willebrand disease (VWD) co-occurring with another likely pathogenic/pathogenic variant in the VWF gene (PMID: 33556167 (2021)). It has also been reported in an individual with Type 3 VWD in the homozygous state with a homozygous canonical splice variant (PMID: 20801902 (2010), 21251206 (2011), 28971901 (2017)). This variant has also been reported individuals with Type 1, Type 1H, and Type 2A VWD (PMID: 26986123 (2016), 27532107 (2016), 28971901 (2017)), as well as in an individual with a bleeding, thrombotic, or platelet disorder (PMID: 31064749 (2019)). The frequency of this variant in the general population, 0.0015 (4/2642 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV000765104	SCV000896324	uncertain significance	von Willebrand disease type 1; von Willebrand disease type 3; von Willebrand disease type 2	2018-10-31	criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000852047	SCV000899540	likely pathogenic	Hereditary von Willebrand disease	2019-02-01	criteria provided, single submitter	research
Laboratory of Hematology, Radboud University Medical Center	RCV002264696	SCV002546247	uncertain significance	von Willebrand disease type 1	2020-12-10	criteria provided, single submitter	research
Baylor Genetics	RCV003147455	SCV003835603	pathogenic	von Willebrand disease type 2	2022-04-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323534	SCV004028805	uncertain significance	not specified	2023-07-11	criteria provided, single submitter	clinical testing	Variant summary: VWF c.1625C>G (p.Ala542Gly) results in a non-conservative amino acid change located in the von Willebrand factor, type D domain (IPR001846) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 250426 control chromosomes (gnomAD). c.1625C>G has been reported in the literature in individuals affected with Von Willebrand Disease (Corrales_2010, Casonato_2016, Veyradier_2016, Sadler_2021, Borras_2017). One patient was reported as putatively compound heterozygous with a pathogenic variant, although other patients were found to have a likely pathogenic variant in cis or without the phase indicated. These data do not allow any conclusion about variant significance. 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: 20801902, 27532107, 26986123, 33556167, 28971901, 21251206, 31064749). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classified it as uncertain significance (n=4), or pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004551444	SCV004117161	uncertain significance	VWF-related disorder	2022-09-09	criteria provided, single submitter	clinical testing	The VWF c.1625C>G variant is predicted to result in the amino acid substitution p.Ala542Gly. This variant has been reported in patients with von Willebrand disease, but has always been reported in a cis configuration with a splice site variant c.533-2A>G making it unclear whether the missense variant p.Ala542Gly is actually a cause of disease (see Corrales et al. 2010. PubMed ID: 20801902; http://www.hemobase.com/vwf/VWF_Database/Mutations/Mutations.html). This variant has also been reported in studies of VWD patients, but it is unclear whether it is a cause of disease within the studied cohort (Veyradier et al. 2016. PubMed ID: 26986123; Table S2 - Sadler et al. 2021. PubMed ID: 33556167). Additionally, the c.1625C>G (p.Ala542Gly) variant was observed in a cohort of individuals with bleeding, thrombotic and platelet disorders, and reported as likely pathogenic (TGP0672, Supplementary Table 3, Downes et al. 2019. PubMed ID: 31064749). This variant is reported in 0.14% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-6167119-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000852047	SCV005399259	uncertain significance	Hereditary von Willebrand disease	2020-05-25	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glycine (exon 14). (N) 0251 - Variant is heterozygous. (N) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (p.(Ala542Thr): 1 heterozygote, 0 homozyotes). (N) 0310 - Variant is present in gnomAD >=0.001 and <0.01 for a dominant condition (194 heterozygotes, 0 homozygotes). (N) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0600 - Variant is located in an annotated domain or motif (VWFD 2 motif; PDB). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0808 - Previous reports of pathogenicity are conflicting. This variant has been reported in multiple patients with type 1, 2A or 3 von Willebrand disease (PMIDs: 26986123, 28971901), however most of them also had another pathogenic VWF variant (PMIDs: 28971901, 27532107, 21251206). It is also reported in ClinVar with conflicting interpretation of pathogenicity. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Mayo Clinic Laboratories, Mayo Clinic	RCV000760113	SCV005408249	uncertain significance	not provided	2023-10-23	criteria provided, single submitter	clinical testing	BP2, BP4, PM1