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Areesha Salman

Areesha Salman

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Disease

Congenital Heart Disease

Inheritance

Autosomal recessive / autosomal dominant / X-linked

Prevalence

Expand
titlePossible sources

Orphanet

Medline Plus Genetics

 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

Variant/Case Evidence: 2.6 points

NM_002941.3(ROBO1):c.355C>T (p.R119*) - 1 point (de novo, NMD+)

  • Present in 3 heterozygotes in gnomAD v4. Highest AF 0.00001098 in South Asian population.

  • 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*) - 0.5 points (de novo, NMD+, removed 0.5 points for targeted sequencing).

  • Present in 11 heterozygotes in gnomAD v4. Highest AF 0.00001339 in African/African American population.

  • 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 - 0.1 points (NMD-, removed points because it was inherited from unaffected mother)

  • Absent from gnomAD.

  • Deletion is in-frame but affects a large portion of the gene (amino acids 58-1581 of 1651)

  • 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 - 1 point (de novo, NMD+)

  • Present in 2 heterozygotes in gnomAD v4. Highest AF 8.761e-7 in European non-Finnish population.

  • Adjacent exon is exon 22/31

  • PMID 36011280

    • 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: 2 points

  • PMID 28592524: Mice harbouring an ENU-induced mutation in Robo1 (Robo1I270T) showed both craniofacial and cardiac anomalies (shortened snout, cleft palate, double outlet right ventricle (DORV) with perimembranous VSD, AVSD, VSD, ASD)

Not included: PMID: 35534675Source:

Clinical Validity Points Total

Source: 4.6 points

Clinical Validity Classification

Expand
titleClassifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

Source: Limited

Molecular Mechanism

Expand
titleMechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

Penetrance

Expand
titleoptions

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

Expand
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 FeaturesSources:

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 varianthttps://docs.google.com/document/d/1XY2_T3IJ7mtVPSrC6dCWmV2gqgqJ2p1laVBGZySK7vM/edit

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

SDSM-2KF, Areesha Salman, 8/20/24