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Andrea Oza

Andrea Oza

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Disease

FORMAT: HEADING 1

Inheritance

Autosomal recessive / autosomal dominant / X-linked

Prevalence

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titlePossible sources

Orphanet

Medline Plus Genetics

 

Source:

Rapid or full curation?

  •  Rapid
  •  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

Clinical Validity Scoring Notes and points

c.2456C>T p. Pro819Leu - absent gnomad.

  • 38348603 - homozygous in family 1 and 2 with Wiedemann- Rautenstrauch syndrome, identified via WES. Per text parents were heterozygous. 2 CASES (deduct for consanguinity, 0 variant points), 1 SEGREGATION

    • Clinical features include anophthalmia, bilateral talipes equinovarus, seizures, global developmental delay, inguinal hernia, microphthalmia, nystagmus, recurrent infections, severe failure to thrive, Sinus tachycardia, and vomiting, arthrogryposis multiplex congenita, motor delay, spasticity, and triangular face with prominent forehead, microphthalmia, bilateral epicanthal folds, low set ears, microstomia, short neck

c.1895G>T p.Cys632Phe - absent gnomad

  • 38348603 - One family with Wiedemann- Rautenstrauch syndrome, consanguineous. 1 CASE (0 variant points = 0.5-0.5 for consanguinity), 1 SEG

c.2474C>G p.S825* - 1 allele gnomad, NMD+

  • PMID: 30323018 - variant found comp het in trans with two other variants, c.1909+22G>A and c.3337–11T>C. However, the text states that an unaffected father is HOM for the two intronic variants, which indicates these variants likely do not cause disease, and c.1909+22G>A has a very high MAF . with 10 homozygotes in gnomAD v4. However, several clinical labs classify c.1909+22G>A as P/LP, and this paper performed cDNA sequencing which showed that c.1800c>t and c.1909+22g>a had a strong additive effect on splicing resulting in exon 14 (e14) skipping. Skipping scoring this variant because there is so much going on on the other allele.

PMID: 30450527 - Phenotype is progeriod.

  • Patient 1 with c.3337-5T>A (6 alleles gnomAD, splice AI 0.02 but per text cDNA shows exon skipping of exon 26, in frame) in trans with c.3337-1G>A (2 allees gnomad, SpliceAI 0.99). Exon is in frame. 0.5 + 2 = 2.5 VARIANT POINTS

PMID: 32582862

  • Patient 2 with c.3337-5T>A and p.R254* (0.005%, 78/1180036 European chr). 0.5 + 2 = 2.5 VARIANT POINTS

PMID: 27612211 - Wiedemann-Rautenstrauch syndrome, also known as neonatal progeroid syndrome

  • c.1909+18G>A; p.(Y637Cfs23) and c.2617C>T; p.(R873*)

Source:

Clinical Validity Points Total

Source:

Clinical Validity Classification

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titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Source:

Molecular Mechanism

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titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

Penetrance

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titleoptions

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

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titleoptions

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Severity

Expand
titleOptions

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

Expand
titleExamples

- 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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