ClinVar Miner

Submissions for variant NM_000552.4(VWF):c.3797C>A (p.Pro1266Gln) (rs61749370)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000086675 SCV001148586 likely pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing
Academic Unit of Haematology, University of Sheffield RCV000086675 SCV000118879 not provided not provided no assertion provided not provided
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678765 SCV000804944 pathogenic von Willebrand disorder 2014-03-26 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000086675 SCV001554036 uncertain significance not provided no assertion criteria provided clinical testing The VWF p.P1266Q variant was identified in the heterozygous or compound heterozygous state in multiple individuals with von Willebrand disease type 2B, including 8 individuals from 4 families; these individuals generally displayed normal multimeric protein patterns, plasma VWF levels, platelet VWF levels, and low bleeding scores (Casonato_2017_PMID:28640903; BorraÃÄs_2017_PMID:28971901; Federici_2009_PMID:18805962; Ahmad_2013_PMID:23179108; Veyradier_2016_PMID:26986123; Casonato_2016_PMID:27532107). The p.P1266Q variant usually results due to gene conversion with the VWF pseudogene and is typically found in combination with other VWF variants. The variant was identified in dbSNP (ID: rs61749370) and ClinVar (classified as pathogenic by John Hopkins Children's Hospital and as likely pathogenic by CeGat Praxis). The variant was identified in control databases in 76 of 281180 chromosomes (2 homozygous) at a frequency of 0.0002703 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 41 of 30468 chromosomes (freq: 0.001346), Other in 3 of 7204 chromosomes (freq: 0.000416), European (non-Finnish) in 24 of 127752 chromosomes (freq: 0.000188), Latino in 5 of 35424 chromosomes (freq: 0.000141), African in 2 of 24944 chromosomes (freq: 0.00008) and East Asian in 1 of 19948 chromosomes (freq: 0.00005), but was not observed in the Ashkenazi Jewish or European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.P1266 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. Functional studies demonstrated that the p.P1266Q variant alone did not affect VWF protein expression or activity compared to wildtype, however the combination of p.V1229G-p.N1231T-p.P1266Q variants caused decreased expression and binding of VWF to GPIba (Ahmad_2018_PMID: 30488424). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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