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Gene-disease assertions not curated here (add link or write note): Loss of function variants cause Pitt-Hopkins syndrome (Definitive in ClinGen)

Disease

Fuchs endothelial corneal dystrophy type 3

Inheritance

Autosomal dominant

Prevalence

 Common: Affects 4% of Caucasian population in US, and 75% are associated w/ triplet repeat expansion

Source: PMID: 31276570

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Clingen - none. GenCC - strong by G2P. HGMD variants/papers in Clinical validity scoring notes.

Clinical Validity Scoring Notes and points

Variant/Case Evidence:

Segregation Evidence:

Case/Control Evidence:

Experimental Evidence:

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Source:

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

Short tandem repeat - CAG in intron 1

  • Normal

  • Pathogenic

  • Cutoff:

Review:

  • Stripy: normal ≤31, pathogenic ≥50

  • Strchive: Normal 10 - 40, Pathogenic ≥50

  • Mayo not available

  • gnomad: Normal ≤ 31, Pathogenic ≥ 50. Note: many alleles >50 repeats.

  • 1676829

  • 21245398

  • 25168903

  • Weiben 2019 PMID: 31276570

    • No interruptions of the expanded CAG repeat was found. But novel variants within the AGG repeats that flank the CAG were found in 2/5 unaffected patients w/ expansions.

    • Table 1, smallest expansion in affected individuals with an expansion is 64 repeats

  • Bhattacharyya 2024 PMID: 38713708

    • Previously demonstrated in large cohort that an expanded copy defined as ≥ 50 copies confers a <76-fold increased risk for developing FECD

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)

Adulthood, 5th-6th decade

PMID: 38713708

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

Age-related cause of vision loss

  • Corneal edema and opacity

Sources: 38713708

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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