Submissions for variant NM_000552.5(VWF):c.6025C>T (p.His2009Tyr)

dbSNP: rs761740133

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001270345	SCV001450570	uncertain significance	von Willebrand disease type 3		no assertion criteria provided	clinical testing	The VWF p.H2009Y variant was not identified in the literature nor was it identified in Clinvar. The variant was identified in dbSNP (ID: rs761740133) and in control databases in 1 of 251230 chromosomes at a frequency of 0.000003980, where it was observed in the European (non-Finnish) population in 1 of 113610 chromosomes (freq: 0.000008802) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.H2009 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356243	SCV001551358	uncertain significance	von Willebrand disease type 2		no assertion criteria provided	clinical testing	The VWF p.H2009Y variant was not identified in the literature nor was it identified in Clinvar. The variant was identified in dbSNP (ID: rs761740133) and in control databases in 1 of 251230 chromosomes at a frequency of 0.000003980, where it was observed in the European (non-Finnish) population in 1 of 113610 chromosomes (freq: 0.000008802) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.H2009 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357164	SCV001552537	uncertain significance	von Willebrand disease type 1		no assertion criteria provided	clinical testing	The VWF p.H2009Y variant was not identified in the literature nor was it identified in Clinvar. The variant was identified in dbSNP (ID: rs761740133) and in control databases in 1 of 251230 chromosomes at a frequency of 0.000003980, where it was observed in the European (non-Finnish) population in 1 of 113610 chromosomes (freq: 0.000008802) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.H2009 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. 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.