chr12-6019180-G-A
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PP2PP3_Moderate
The NM_000552.5(VWF):c.4238C>T(p.Pro1413Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1413Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_000552.5 missense
Scores
Clinical Significance
Conservation
Publications
- hereditary von Willebrand diseaseInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- von Willebrand disease type 2BInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- von Willebrand disease 2Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
- von Willebrand disease 1Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
- von Willebrand disease type 2AInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- von Willebrand disease type 2MInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- von Willebrand disease 3Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- von Willebrand disease type 2NInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152136Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.00000796 AC: 2AN: 251134 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461656Hom.: 0 Cov.: 99 AF XY: 0.0000124 AC XY: 9AN XY: 727142 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152136Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74314 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:1Other:1
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The VWF c.4238C>T (p.Pro1413Leu) variant has been reported in the published literature in multiple individuals with Von Willebrand disease type 1 (PMIDs: 16985174 (2007), 17190853 (2007), 18230755 (2008), 21534937 (2011), 22871923 (2012), 27076201 (2016), 28971901 (2017), 31249928 (2018), and 33134807 (2020)). In vitro expression studies indicated that this variant has no effect on vWF protein function (PMID: 27483487 (2017)) but further studies are required to determine the global effect of this variant on vWF protein function. The frequency of this variant in the general population, 0.000011 (3/282514 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
VWF-related disorder Uncertain:1
The VWF c.4238C>T variant is predicted to result in the amino acid substitution p.Pro1413Leu. This variant has been reported in individuals with Von Willebrand disease 1 (Goodeve et al. 2007. PubMed ID: 16985174; Manderstedt et al. 2018. PubMed ID: 31249928; Dubois et al. 2020. PubMed ID: 33134807). In Manderstedt et al., this variant occurred together with another variant (p.Gly1672Arg), indicating these two variants occur on the same haplotype (Manderstedt et al. 2018. PubMed ID: 31249928). Functional studies using protein expression in cell culture found that the p.Pro1413Leu substitution did not significantly affect protein function (Berber et al. 2016. PubMed ID: 27483487). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-6128346-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at