Inheritance

autosomal dominant

Prevalence

 COMMON

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

No ClinGen curations, limited for CHD by Ambry, limited by BabySeq (cites 24587289, 24476948). HGMD papers listed in clinical validity.

Clinical Validity Scoring Notes and points

• 24587289 - see table 1 for list of variants. Instead of scoring all of these, assuming they all would get their full points, we would only reach 1.3 variant points since this is a rare condition and they are al VUS (0.1x13). Fig 2 does not show convincing evidence that any of the variants overexpressed behaved differently than WT in cell migration (possibly mut 2, 4 and 5 which correspond to Mutant 2, Met360Lys, ; Mutant 4, Glu418Lys; Mutant 5, Asp554Val). fig 3c shows Glu418Lys localizes to both cytoplasm and nucleus. So another 0.5 variant points. 1.8 points total

  Open

  

• 32368696 - part of WAVE2 complex. c.4154T>C p.L1385P listed as de novo in case w/ LVOs. Absent gnomAD. 0.6 points.

PMID: 15710412 - Homozygous null mouse model is embryonic lethal and the heart is incompletely developed. Adult het mice did not display any abnormaliites. Doesn’t match proposed inheritance, but scoring some evidence for the abnormal heart development. 0.5 point.

PMID: 20199662 - Another mouse model homozygous gene trapped (targets 1 isoform) embryos showed defects in the brain, heart, and placental blood vessels. 0.5 point.

Paper in biorxiv from 2021 (: https://doi.org/10.1101/2021.02.11.430763;) indicate dlc1 is important for vascular development in zebrafish. Loss of dlc1 (dlc1 null embryos) negatively affected the lumenization of the first aortic arch arteries and the lateral 9 dorsal aortae. Since animals are null, scoring as 0.5 point animal model

Source:

Clinical Validity Points Total

4.4 points

Source:

Clinical Validity Classification

Limited.

Source:

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