Inheritance

Autosomal dominant

Prevalence

Source:

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

GenCC: vertebral hypersegmentation and orofacial anomalies (Strong- G2P 12/7/2021; Limited- Invitae 12/23/2020)

OMIM: AD ?Vertebral hypersegmentation and orofacial anomalies (MIM#619122)

HGMD:

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

• PMID: 31215115 (Cox 2019)- 1 proband with p.Arg298Gln variant (0.5 pts)

• PMID: 34113007 (Ravencroft 2021)- 6 probands total; Pt 1: de novo p.Y336* (2.5 pts), Pt 2: inherited p.Q147Gfs*82 (2 pts), Pt 3: de novo p.T319Nfs*5 (2.5 pts), Pt 4: inherited p.N94Rfs*47 (2 pts), Pt 5: de novo p.R295P (1 pt), Pt 6 de novo p.E306K (1 pt)

Segregation Evidence:

• PMID: 31215115 (Cox 2019)- Large family with p.Arg298Gln found in a proband and segregated in 4 additional affected family members.  

Case/Control Evidence:

Experimental Evidence:

• PMID: 34113007 (Ravencroft 2021)- gdf11 loss-of-function in Zebrafish present with overlapping facial phenotype (2 pts)

Source:

Clinical Validity Points Total

>12 pts

Source:

Clinical Validity Classification

Source:

Definitive (12pts)

Molecular Mechanism

Loss of function

Several papers suggest: Loss of Function. It is predicted that the missense variants impacting the RXXR motif behave like LOF because TGF-B domain is not cleaved. PMID: 34113007 (Ravencroft 2021)

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