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c.598C>T p.Arg200Trp - Low frequency. gnomad v4 0.0004661 54/91080 South Asian with 1 homozygote REVEL: 0.867.
12415268 (2002)- Chuvash polycythemia is endemic to Chuvash Autonomous Republic of the Russian Federation. Using presumed founder effect, localized the gene associated with Chuvash polycythemia and found homozygous Arg200Trp VHL as the molecular basis of disease. Fig 1 shows segregations. 71 blood samples from 11 families including 20 individuals with polycythemia and 51 relatives. Per main text the Arg200Trp variant perfectly cosegregated in all 20 affected individuals and all obligate hets were het only. 20 AFFECTED AR SEGS. In EBV transformed lymphoblasts, no difference in VHL expression, but expression of HIF1A was greater in affected individuals compared w/ controls. In 786-O cells (a VHL-null carcinoma line), cotransfected cells - Arg200Trp-mutant VHL was less effective in inhibiting reporter gene transcription under non-hypoxic conditions, indicating it reduces the rate of degradation of HIF1a. Increased expression of EPO mRNA was observed in lymphoblasts from affected individuals. Supporting fxnl, NO FEATURES OF VHL OBSERVED IN ANY INDIVIDUALS. 1.5 VARIANT POINTS (FOR CASES), 1 POINT FUNCTIONAL ALTERATION, 3 POINTS SEGREGATION
PMID: 17992257 - Homozygous mouse model - Homozygous mice show polycythemia highly similar to human disease. Activity of HIF proteins, specifically the HIF-2α isoform, was upregulated in ES cells and tissues from VhlR/R mice. NON-HUMAN MODEL ORGANISM 2 POINTS
29891534 (2018) - A cryptic exon 1 deep in intron 1 is naturally expressed in many tissues and in this study they found mutations in this exon in 7 families with erythrocytosis.
c.340+770T>C (2 alleles gnomAD v4)
Patient F1-II.1 cmp het with c.429C>T Asp143Asp
Patient F2, F3-II.1 and -II.2, with c.598C>T p.Arg200Trp
c.429C>T Asp143Asp - 4 alleles gnomAD v4. RT-PCR showed a strong decrease of the E1E2E3 isoform and an upregulation of E1E3 (fig 5). Homozygous in family 9 and 10. 0.5 POINTS
12844285 (2003)
574C>T(P192A) - 1 allele gnomAD, REVEL: 0.897. Cmp het with Arg200Trp in patient 4. 0.5 points.
562C>T Leu188Val - 39/1614072 alleles gnomAD, REVEL: 0.796. Cmp het with Arg200Trp in patients 5 and 6 (unrelated). 0.5x2 = 1 point.
c.571C>G p.(His191Asp) - 1 allele gnomAD, REVEL: 0.712. HOM in patient 7. 0.5x2 = 1 point.
At least moderate, stopped curation once I reached moderate in the interest of time.
Source: 12844285, 29891534, 12415268
MolecularMechanism
Loss of function
Gain of function
Dominant negative
Unknown
Other
Unknown, mostly missense variants.
Penetrance
Complete (100%)
High (≥80%)
Moderate (<80% and >20%)
Low (≤20%)
(list source/PMID)
Source:
Age of Onset
Congenital
Pediatric
Adolescent
Adulthood
Late adulthood
(list source/PMID)
Severity
Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete. Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high. Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced. Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low. None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.
- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).
- Variable expression or severity: The severity and expressivity of the disorder is highly variable, even within families. - If multiple conditions associated with the gene: It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).
- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited
VHL-related familial erythrocytosis is an autosomal recessive disease characterized by an increased number of red blood cells, which can present with symptoms such as headaches, dizziness, nosebleeds and shortness of breath. Hemoglobins and serum erythropoietin concentrations are elevated. There is an increased risk of vertebral hemangiomas, varicose veins, cerebrovascular events, and peripheral thrombosis (PMID: 15599750, 14726398). The VHL gene is also associated with autosomal dominant von Hippel-Lindau syndrome(VHL); however, the variants that cause familial erythrocytosis are distinct and individuals are not reported to have clinical features of VHL (PMID: 12415268, 14726398).
Case ID, Curator name, Date, Jira ticket link
Andrea Oza Accession ID: D-060203242-BH-3965-P-A, 01.16.2024