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  • Edited 02.27.2024 to add variant found in E3740147955 and to add exon numbering to the variants previously scored ***use caution, many alternate transcripts and they also differ between hg19 and hg38, with most having variable expression of exons 6 and 7 (based on NM_001025366.3)

  • Gene-disease assertions not curated here (add link or write note):

Disease

Congenital heart defects

Inheritance

Autosomal dominant

Prevalence

 Common

Source:

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen (dosage) - little evidence for haploinsufficiency / triploinsufficiency. No GenCC curations. HGMD entries below.

Clinical Validity Scoring Notes and points

HGMD: NM_001025366.3

c.655G>T p.E219* (exon 2)- absent gnomAD. NMD+, PMID: 30232381 - reported as Glu39* in proband TOF241 with TOF, RAA, bicuspid pulmonic valve; short stature, obesity; learning difficulties; depression and/or anxiety; stillborn offspring. 1 POINT (COMMON)

c.454C>T p.R152* (exon 1) - absent gnomAD, NMD +, PMID: 20420808 - in patient 2 with Left ventricular outflow tract obstruction BAV, AVS, CoA,PDA, ascending aorta dilation. Also inherited from unaffected family members, and they only sequenced VEGFA, so would decrease points for both. 0.5 POINT

c.19_22dupGACA p.(Thr8Argfs*78 (exon 1) - variant in 0.04% (23/39188) East Asian chr gAD v4. PMID: 20420808 - Present in patient with coarctation of the aorta, VSD and PDA. High MAF, also inherited from unaffected family members, and they only sequenced VEGFA, will not score points for this variant.

c.998G>A p.R333Q (exon 6) - 7/44788 East Asian chr. REVEL score is not in gAD. PMID: 20420808 - Found in one proband with coarctation of the aorta and vsd, but variant inherited from unaffected family members, and they only sequenced this gene. Deduct points. 0.5 POINT

c.973C>T p.R325* (exon 6) - 0.002% (35/1156678) European alleles gnomAD. PMID: 22067973 - found in a patient with isolated tricuspid aortic valve stenosis, but inherited from unaffected parent, VEGFA only gene sequenced. Deduct points. 0.5 POINT

Experimental Evidence:

  • PMID: 33620155 (2021) - increased VEGF applied to quail embryos shown to lead to impaired heart tube elongation accompanied by diameter expansion. VEGF treatment increased the rate of cardiac malformations in surviving embryos. Shows some potential impact of VEGF and congenital heart defects, but applying endogenous VEGF is not replicating the LOF model proposed in humans (based on the variants reported above). Non-human model organism 0.5 points

  • PMID: 15601856 (2005) - VEGF-A is part of the vascular endothelial growth factor signaling system, which is likely involved in the migration of hemangioblast precursor cells in the fetal trunk during early embryogenesis. This study helps support that VEGF-A is important for VEGF signaling during embryogenesis, but isn’t specific to cardiac defects, therefore downgraded the points.

    • In mouse embryos, using RT-PCR and IHC to assess expression, found that VEGF-A is dominant in the anterior portion of the embryo, whereas VEGFR1 and 2 are expressed in the posterior (fig 2 and 3). 0.1 point expression.

    • VEGFA guides VEGFR cells in vitro - whole embryo cultures were treated with different concentrations of VEGFA in different corners of the cell culture wells, and VEGFA at 40ng/ml was most effective (fig 4). VEGFR-positive cells collected from embryos were placed on cover glass and placed next to a spot on the cover glass where cells rom the anterior or posterior region of the embryos had been seeded. VEGFR-positive cells migrated to cells obtained from the anterior portion, and this migration was eliminated by neutralizing anti-mouse VEGFA antibody. VEGFR-positive cells did not migrate toward cells obtained from the posterior region of embryos. (Fig 5). 0.1 point protein interaction

    • VEGF-A heterozygous (+/−) mice showed embryonic lethality due to multiple defects in vascular structure formation (6, 13

  • Carmeliet 1996 PMID: 8602241 - Targeted inactivation of one or both VEGF allele in embryos that were generated by aggregation of embryonic stem cells with tetrapoid embryos. The dorsal aorta was poorly developed in VEGF+/- tetraploid embryonic stem cell dereived embryos. endothelial cells lined a much smaller lumen than normal, especially in the anterior part of the embryo (Fig. 2b, c). At 8.5 d.p.c. the dorsal aorta was missing over its entire length in VEGF-/- embryos. However, no VEGF+/- offspring were obtained (embryonic lethal). VEGF -/- were also embryonic lethal. Fewer endothelial cells lined the smaller lumen of the dorsal aorta in the anterior part of F1 VEGF+/- than VEGF+/+ embryos. Ink injection to view the dorsal aorta and head vessels showed no connection between the heart and the vessel system in VEGF- 1- T-ES cell-derived embryos (Fig. 3c, d). Yolk sac of F1 VEGF +/- embryos displayed an irregular plexus of small vessels but no larger collecting vessels (Fig. 3f, i). 1 point non-human model organism.

  • Ferrara 1006 PMID: 8602242 - Loss of a single VEGF allele is lethal in the mouse embryo betweens days 11 and 12. Angiogenesis and blood-island formation were impaired, resulting in several developmental anomalies. VEGF+/- embryonic stem cells were used to gemerate chimeric mice. Observed a defect in blood supply of the yolk sac in several embryos at E9.5-11.5 (Fig. 3a). The VEGF+I- embryos exhibited several anomalies23 (Fig. 3). In the cranial region, the branchial arches were poorly developed and unsegmented. The forelimb buds were positioned at their earlier caudal location and were unsegmented. Also, the forebrain region appeared significantly underdeveloped (Fig. 3b,g). In the heart region, the common atrium and primitive ventricle were developmentally delayed23, the dorsal aortae were rudimentary, and the thickness of the ventricular wall was markedly decreased (Fig. 3b, c,g, h )

  • PMID: 10229225

  • PMID: 37569543

  • PMID: 28230770

  • PubMed: 11331753

  • PubMed: 11509733

  • PubMed: 12539040

Internal cases:

E3740147955 - ENSP00000361125: p.His362IlefsTer39 aka NM_001025366.3(VEGFA):c.1079del p.gly360Alafs*41. Variant is located in a region that is not expressed in most transcripts, and has a really low pext score (0) in all tissues and in cardiac tissues in gnomad v2. Proband with eczema, laryngomalacia, patent foramen ovale, right aortic arch w/ mirror image branching, tricuspid regurgitation, vasuclar ring, double aortic artch and atelectasis. In addition, this variant has a somewhat high maf (0.07%) 67/74948 alleles in AFrican’African American with 3 HOM in gAD v4. Due to uncertain expression of this part of the protein and high maf, not scoring for now.

E3730537808 - NM_001025366.3(VEGFA):c.735C>A p.(Tyr245*) (exon 3) - this variant is absent gnomad v2, expressed in all available transcripts. Patient phenotype - small for GA, abnormal heart morphology, atrial septal defect, patent ductus arteriosus, biscuspid aortic valve, total anomalous pulmonary venous return, abnormal morphology of the great vessels. PEXT score for this exon is good. Adding 1 point.

Clinical Validity Points Total

4 point

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Limited

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

N/A LIMITED EVIDENCE

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

 Options

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.

Clinical Features

Sources:

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

 Examples

- 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

Case ID, Curator name, Date, Jira ticket link

E3730537808, Andrea Oza, 02.06.24

Updated curation to add internal cases, as another variant found in E3740147955 - Andrea Oza 02.27.2024

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