Inheritance

autosomal dominant

Prevalence

 1/100

Source: About Congenital Heart Defects

Rapid or full curation?

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.

Segregation Evidence: N/A

Case/Control Evidence: N/A

Experimental Evidence: 2 points

• PMID 28592524: Mice harbouring an ENU-induced mutation in Robo1 (Robo1^I270T) showed both craniofacial and cardiac anomalies (shortened snout, cleft palate, double outlet right ventricle (DORV) with perimembranous VSD, AVSD, VSD, ASD)

Not included: PMID: 35534675

Clinical Validity Points Total

4.6 points

Clinical Validity Classification

Limited

Molecular Mechanism

Loss of function

Penetrance

(list source/PMID)

Age of Onset

(list source/PMID)

Severity

Clinical Features

HPO Terms

https://hpo.jax.org/app/

Gene SOPs & Notes

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

Curation Summary

Case ID, Curator name, Date, Jira ticket link

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