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

  • AR neurooculorenal syndrome

  • AD pituitary hormone deficiency/pituitary stalk interruption syndrome

Disease

Congenital Heart Disease

Inheritance

Autosomal recessive / autosomal dominant / X-linked

Prevalence

 1/100

Source: https://www.cdc.gov/heart-defects/about/index.html#:~:text=Congenital%20means%20they%20are%20present,has%20a%20critical%20heart%20defect.

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

No assertions for isolated congenital heart disease. In scope for ClinGen Congenital Heart Disease GCEP.

Clinical Validity Scoring Notes and points

NM_002941.3(ROBO1):c.355C>T (p.R119*)

  • Present in 3 heterozygotes in gnomAD v4.

  • Stop occurs in exon 4/31

  • PMID: 28592524

    • Observed in a 14yo male with ToF, and dysmorphic features (Dolichocephaly, micrognathia, prominent nasal root, high arch palate, crowding teeth). De novo, found on trio WES and confirmed by Sanger. Normal chromosomal microarray. An additional de novo missense variant was found in KLHL38 (c.356T>C, p.L119P), not associated with cardiac development or human disease per authors.

NM_002941.3(ROBO1): c.928C>T (p.R310*)

  • Present in 11 heterozygotes in gnomAD v4

  • Stop occurs in exon 8/31

  • PMID: 28592524

    • Observed in an 8yo female patient with VSD and congenital diaphramatic hernia. De novo, identified on targeted sequencing of ROBO1 and confirmed by Sanger. Normal chromosomal microarray.

418 kb deletion (Chr3:78653579–79071345; hg19) affecting exons 4-29

  • PMID: 28592524

    • Observed in a 4 month old patient with VSD, left vocal cord paresis, minimal facial dysmorphism. Variant was inherited from mother (unaffected). Same as pt 333322 in DECIPHER. Identified on microarray.

ROBO1 c.2883-1G>T

  • Present in 2 heterozygotes in gnomAD v4.

  • Adjacent exon is exon 22/31

  • Observed in a patient with COA, VSD, PDA, and congenital hydronephrosis. De novo. Found through WES (assuming trio WES based on context but this is not stated explicitly). Parents were non-consanguineous.

Variant/Case Evidence:

Segregation Evidence: N/A

Case/Control Evidence: N/A

Experimental Evidence:

Not included: PMID: 35534675

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

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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