Inheritance

Autosomal dominant

Prevalence

 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?

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. (0.6 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. (0.6 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. (0.6 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

1.8

Clinical Validity Classification

Limited.

Molecular Mechanism

Penetrance

(list source/PMID)

Age of Onset

(list source/PMID)

Severity

Clinical Features

Sources:

HPO Terms

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

Gene SOPs & Notes

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

Curation Summary

Case ID, Curator name, Date, Jira ticket link

Case ID: SDSM-8F/SDOR-55/PDO-33275/E3710449173

Curator: Areesha Salman

Date: 12/8/2023

Updated: 12/15/2023, applied +0.5 points for de novo variants instead of +0.25 based on correction to SOP.