Inheritance

Curated for both AD and AR. AD actually had more scorable evidence.

Prevalence

 Rare (1/10,000)

Source: Heterotaxy syndrome: MedlinePlus Genetics

Rapid or full curation?

ClinGen / GenCC / BabySeq / HGMD / OMIM

No ClinGen curations. GenCC - Strong (Invitae), limited (Ambry). BabySeq (limited). Curated HGMD variants below.

Clinical Validity Scoring Notes and points

• Constraint - not issense constrained (z=3.05). Moderate LOF constrained, LOEUF = 0.41.

• Curated DM variants only that are associated w/ heterotaxy, laterality defects or congenital heart disease.

• NM_001106.4:c.92A>G;p.(Tyr31Cys). Absent gnomAD v4, REVEL 0.95.

  • PMID: 37644014 in family F7988. Variant is homozygous which doesn’t fit proposed inheritance. Per supplement data 1, phenotype is Supernumerary nipple; Supernumerary ribs; Dextrocardia; Abnormal facial shape; Abnormal heart morphology (complex heart disease); Pulmonary situs ambiguus; Asplenia; midline liver; Bilateral talipes equinovarus; Hypoplasia of the corpus callosum; Wide anterior fontanel; Micrognathia. There was no further segregation / variant information provided. 0.5 POINTS FOR AR

• NM_001106.4: c.119G>A; p.R40H - frequency too high in gnomAD, did not score papers. 1.2% in AA (963/75038) with 12 homozygotes. 2 star B/LB in ClinVar.

  • PMID: 9916847

• NM_001106.4: c.1057G>T p.G353W, absent gnomAD v4. REVEL 0.72

  • PMID: 30293987 - variant reported in patient with congenital heart diease but also found in asymptomatic mother (family 150650086). This proband also had a HOM variant in DOCK6 (AR Adams-Oliver syndrome, which has CHD. No points can be applied for this family given the alternate explanation of disease.

• NM_001106.4:c.1480G>A p.V494I - 14 alleles gnomAD v4 [0.0005% (12/1180020] European non-FInnish chr.

  REVEL: 0.374

  • PMID: 9916847 - cant access, but per OMIM in a patient with left-right axis malformation. 0.5 points for AD.

• NM_001106.4: c.925C>T Arg309Cys (DM? in HGMD), frequency in gAD higher than expected for AD, 0.002% (5/91080) S. Asian, also present in other populations. REVEL: 0.594

  • PMID:35547246Found in patient w/ laterality defect, but Patient also HOMOZYGOUS c.350A>G p.Asp117Gly in CCDC39. no points

• PMID: 30622330 - this paper had several variant marked as DM?

  • NM_001106.4:c.1147C>T NP_001097.2:p.Arg383Cys - absent gnomAD. Family ID: LAT1543 Observed in patient w/ laterality defect and segregated in 4 affected family members. The diagnosis in the proband was a venous anomaly per table 1, but reviewing supplement 1 the proband had atrial septal defect, Interrupted IVC, TAPV. “Left superior vena cava to coronary sinus, MR,PR, TR, Right ventricular hypertrophy, Right ventricular dilation or enlargement, Dilatation of the main pulmonary artery Unusual systemic venous return from the lower extremities and abdomen with a small (b”. AD EVIDENCE: 0.5 VARIANT POINT, 4 AD SEGREGATION (0 SEGREGATION POINTS)

  • NM_001106.4:c.527C>G P176R in a patient w/ conotruncal defect per table 1, in LAT1333. Per table s1, DORV with the PA arising slightly more anterior than the aorta. BILATERAL GRADE IV VESICOURETERAL REFLUX. but frequency looks too high with 479/1180000 alleles in gAD v4 European chr. gnomAD . No

Mouse:

• Targeted disruption of mouse Acvr2b gene results in abnormal left-right developments in homozygous knockout. PMID: 9242489. SCORE 2 POINTS AR, 1 POINT FOR AD

• A knockout mouse of Pitx2, the downstream targeted of Acvr2b, showed an identical phenotype to Acvr2b homozygous knockout mouse PMID: 10499586. Scoring under protein interaction. 1 POINT FOR AR, 0.5 POINT FOR AD.

Pubmed search:

• no additional papers found to curate

Clinical Validity Points Total

AD EVIDENCE: 2.5 POINTS

AR EVIDENCE: 3.5 POINTS

Clinical Validity Classification

LIMITED

Molecular Mechanism

Loss of function / Gain of function / Dominant Negative

Penetrance

(list source/PMID)

Source:

Age of Onset

(list source/PMID)

Severity

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

Case ID, Curator name, Date, Jira ticket link