Paediatric disorders - additional genes

Gene: ACVR2B

Green List (high evidence)

PMID: 9916847 Kosaki et al., 1999
Report of 3 patients who are heterozygous for variants p.(R40H), p.V494I (1999 paper).
ACVR2B:c.1480G>A p.Val494Ile is rare in gnomAD v4 (14 alleles reported, no homozygotes, MAF = 0.00003378).
ACVR2B:c.119G>A, p.Arg40His mutation has 4 homozygotes in the population (gnomAD) and >350 heterozygotes - too common for a rare dominant disorder.

PMID: 21864452 Ma et al., 2011
Two unrelated patients with heterotaxy and a recurring missense (p.R40H). Unaffected mothers are carriers = variant did not segregate with disease.

PMID: 30622330 Li et al., 2019
Pedigree with a heterozygous missense variant in ACVR2B and heterotaxy. Family 1: c.1147C>T, p.Arg383Cys missense variant in ACVR2B was inherited from an affected parent, clear segregation of the variant with five affected individuals from three generations. The variant is not present in gnomAD v4, and it is classified as LP in ClinVar.

PMID: 35547246 Antony et al., 2022
Family SI-47 - proband with Situs inversus totalis had a heterozygous ACVR2B variant c.925C>T, p.Arg309Cys and a homozygous c.350A>G, p.Asp117Gly variant in CCDC39. CCDC39 is associated with recessive Ciliary dyskinesia, primary, 14, OMIM:613807. Effect of each variant is unclear. The p.Arg309Cys variant is rare in gnomAD v4, with 30 alleles reported and no homozygotes (MAF = 0.00005490); VUS in ClinVar.

Functional evidence:
PMID: 9242489 Oh & Li 1997 - knockout acvr2b -/- mice die after birth with complicated cardiac defects including randomized heart position, malposition of the great arteries, and ventricular and atrial septal defects; the heart anomalies are associated with right pulmonary isomerism and splenic abnormalities.
PMID: 17849440 Goto et al., 2007 - The acvr2b+/− mice were revealed to be normal and viable; left–right patterning defects seen in some of the (acvr2b+/−smad2+/−) mice - digenic inheritance?
PMID: 21864452 Ma et al., 2011 - Activin receptor IIB (Acvr2b) is expressed asymmetrically along left-right axis in mouse and chick

The gene is associated with AD Heterotaxy, visceral, 4, autosomal, MIM:613751 in OMIM. ACVR2B has not been curated in ClinGen and it is limited in Gene2Phenotype.

Created: 20 Mar 2026, 3:51 p.m. | Last Modified: 23 Mar 2026, 10:22 a.m.

Panel Version: 7.37

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Heterotaxy, visceral, 4, autosomal, OMIM:613751

Publications

• 9916847
• 21864452
• 30622330
• 35547246

Green List (high evidence)

Comment on list classification: Meets criteria for green rating under 100K - awaiting higher level sign off re GMS indication

Created: 7 Aug 2019, 1:48 p.m. | Last Modified: 7 Aug 2019, 1:48 p.m.

Panel Version: 0.26

Three unrelated cases of left-right axis malformations, including cardiac anomalies e.g. left atrial isomerism
Sources: Literature

Created: 7 Aug 2019, 1:47 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Heterotaxy syndrome Heterotaxy, visceral, 4, autosomal, 613751

Publications

• 9916847