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Areesha Salman

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Disease

Congenital Heart Disease

Inheritance

Autosomal dominant

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 Generally quoted as 1/100 (common).

Source: https://www.cdc.gov/ncbddd/heartdefects/data.html#:~:text=Number%20of%20U.S.%20Babies%20Born,year%20in%20the%20United%20States.

Rapid or full curation?

  •  Rapid
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Not in ClinGen or BabySeq.

GenCC: No submissions for AD CHDs. Three submissions for AR developmental and epileptic encephalopathy (strong by Invitae, moderate by Illumina, supportive by Orphanet).

OMIM: AR Developmental and epileptic encephalopathy.

HGMD: Curated variants below.

Clinical Validity Scoring Notes and points

Many repeat cases using the Pediatric Cardiac Genetics Consortium (PCGC).

CAD c.364C>T p.R122W

  • Absent from GnomAD v4.

  • REVEL: 0.947

  • PMID 26785492: Observed in 1-00129. De novo. Patient had a complex cardiac phenotype including: ASD, VSD, transposition of the great arteries, hypoplastic pulmonary arteries, parachute mitral valve, pulmonary stenosis, developmental delay, learning difficulty, macrocephaly, congenital Blindness, retinitis pigmentosa, chorioretinal atrophy, undescended testis, congenital scoliosis, small stature, static encephalopathy. (0.35 points)

  • PMID: 28991257, PMID: 28191890, PMID: 31941532, PMID: 32368696: Looks like the same case as PMID 26785492.

CAD c.2782C>G p.L928V

  • Absent from GnomAD v4.

  • REVEL: 0.551

  • PMID 26785492: Observed in 1-04215. De novo. Patient had atrial septal defect, left aortic arch, developmental delay, esotropia, umbilical hernia, abnormal thumb, cafe au lait spots, hemangioma. (0.35 points)

  • PMID: 28991257, PMID: 28191890, PMID: 31941532, PMID: 32368696: Looks like the same case as PMID 26785492.

CAD c.6432G>A p.M2144I

  • Absent from GnomAD v4.

  • REVEL: 0.645

  • PMID 26785492: Observed in 1-00200. De novo. Patient had transposition of the great vessels, tricuspid regurgitation, tricuspid valve abnormality, ventricular septal defect, ventricular inversion. (0.35 points)

    learning disabilities

  • PMID: 28991257, PMID: 28191890, PMID: 31941532, PMID: 32368696: Looks like the same case as PMID 26785492.

CAD p.R842fs (2:27454972G>GT)

  • PMID: 28991257: Patient 1-03753 with conotruncal defect, EM, and NDD. Heterozygous, transmitted.

  • Not scored.

CAD p.S1872fs (2:27463800CCT>C)

  • PMID: 28991257: Patient 1-13318 with conotruncal defect, EM, unknown NDD. Heterozygous, transmitted.

  • Not scored.

Clinical Validity Points Total

1.05

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Limited.

Source:

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 varianthttps://docs.google.com/document/d/1XY2_T3IJ7mtVPSrC6dCWmV2gqgqJ2p1laVBGZySK7vM/edit

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

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