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Andrea Oza

Andrea Oza

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Disease

Congenital heart defects

Inheritance

Autosomal dominant

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 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

c.655G>T p.E219* - 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* - 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 - 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 - 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* - 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

PMID: 33620155 - 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). 0.5 points

Clinical Validity Points Total

2.5 3 point

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Limited

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

Penetrance

Expand
titleoptions

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

Expand
titleoptions

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

Expand
titleOptions

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

Expand
titleExamples

- 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

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