Inheritance

Autosoma dominant

Prevalence

 Tetrology of fallot - 1/3000 births

Overall CHD is 1/110

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

Not in ClinGen, GenCC, babySeq. Curated HGMD variants below.

Clinical Validity Scoring Notes and points

Gene is not constrained for missense or pLOF variants. All of the variants in HGMD are in gnomAD (see each one below). I scored these generously despite the MAF, but you could argue that some of the variants I scored should not get any points at all. Scored VSD as common phenotype, but TOF or complex CHD such as coarctation as rare phenotype.

Werner 2016 PMID: 26694203

• c.79_87dup9 p.P27_D29dup - 0.001% (20/1011174) European chr, gAD v4. CADD: 9.95. in a patient with conoventricular VSD, inherited from father. Common phenotype 0.1 point, but not scoring due to MAF.

• c.310G>A p.E104K - 0.004% (65/1117728) European chr in gAD v4. REVEL score 0.386. Found in a patient with tetrology of Fallot, inherited from mother per table 2. Downgrading due to MAF to 0.1 point

• c.359T>C p.L120P - 0.3% (144/37088) East Asian in gAD v4. REVEL 0.88. in a patient with conoventricular VSD. No points, MAF too high.

• c.436_437delAG p.L147Pfs*9 - 0.017% (19/69736) African/African American alleles gAD v4, NMD+ in a patient with conoventricular VSD. 1 point for common phenotype (VSD), downgrading to 0.5 due to MAF. 0.5 point

• c.503A>G p.D168G - in patient with conoventricular VSD. 2.7% (1929/67414) African/African American alleles gAD v4. Did not score, MAF too high.

• c.804G>C p.K268N - in patient with VSD, coarctation of aorta, aortic atresia. Inherited from mom. 0.0005% (2/60016) Admixed American gAD v4. REVEL 0.177 0.5 point

Zhang 2017 PMID: 28677747

• c.352C>T p.Q118* - 2 alleles gnomAD, but covered in <50% of individuals in exome data. NMD+ in a patient with double outlet right ventricle and a VSD. They performed Sanger sequencing for MESP1 only. Parents were negative, variant was reported de novo. A dual luciferace reporter assay had reduced activation when expressed alone, but looking at fig 4 when co-expresse with wt it doesn’t look like there was a difference between wt-Q118X and wt-MESP1 alone. Downgrading to 1 point due to coverage in gnomAD and only Sanger performed, but adding 0.5 for de novo 1.5 POINTS

Reuter 2021 PMID: 34328347

• c.370G>T p.E124* - 0.004% (32/1143200) European non-Finnish alleles gnomAD. In a patient with TOF. NMD+. 2 point, but downgrading to 1 due to MAF. 1 POINT

Clinical Validity Points Total

3.6

Clinical Validity Classification

Limited

Molecular Mechanism

Loss of function / Gain of function / Dominant Negative

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

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

Case ID, Curator name, Date, Jira ticket link