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Gene-disease assertions not curated here (add link or write note):

Disease

Vertebral hypersegmentation and orofacial anomalies

Inheritance

Autosomal dominant

Prevalence

 

Source:

Rapid or full curation?

  • Rapid
  • Full

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

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Source:

Definitive (12pts)

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

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

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

 Options

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 variant

Curation Summary

 Examples

- 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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