Laterality disorders and isomerism

Gene: ACVR2B

Green List (high evidence)

Comment on list classification: There are 3 unrelated individuals reported with heterotaxy and heterozygous missense variants in ACVR2B. Animal models are supportive of gene-disease association, though in homozygous knockouts only (heterozygous knockout mice are reportedly normal). Additional cases have been reported harbouring the p.Arg40His variant, which is too common to cause dominant disease (not counted). Based on available evidence, this gene should be promoted to Green at the next update.

Created: 14 Apr 2026, 1:28 p.m. | Last Modified: 14 Apr 2026, 1:28 p.m.

Panel Version: 4.11

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: 14 Apr 2026, 1:20 p.m. | Last Modified: 14 Apr 2026, 1:20 p.m.

Panel Version: 4.10

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Heterotaxy, visceral, 4, autosomal, OMIM:613751; heterotaxy, visceral, 4, autosomal, MONDO:0013403

Publications

• 9916847
• 21864452
• 30622330
• 35547246

Red List (low evidence)

Limited evidence in literature:

Variants reported on OMIM:

PMID 9916847 - c.119G>A in 397 alleles in gnomAD, prevalence not consistent with AD disease

Other variant in paper c.1480G>A would class as VUS.

Created: 25 Nov 2019, 11:36 p.m. | Last Modified: 25 Nov 2019, 11:36 p.m.

Panel Version: 0.51

Phenotypes
OMIM 613751 Heterotaxy, visceral, 4, autosomal

Publications

• 9916847

Green List (high evidence)

Comment on list classification: Downgraded from Green to Red after expert review. Change of rating will be included in update with Test Group to enable further comment/review if required before sign off.

Created: 27 Nov 2019, 12:30 p.m. | Last Modified: 27 Nov 2019, 12:34 p.m.

Panel Version: 0.131

From review Panel Name: Familial non syndromic congenital heart disease. Panel version: 1.8 4 Jul 2017, 7:24. Review made by: Helen Brittain (Genomics England Curator). Evidence:Green List (high evidence)
Comment: Three unrelated cases of left-right axis malformations, including cardiac anomalies e.g. left atrialisomerism in PMID:9916847. Mode of Inheritance : MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown. Phenotypes : Heterotaxy syndrome; Heterotaxy, visceral, 4, autosomal, 613751; Visceral Heterotaxy; Heterotaxy, Visceral, 4, Autosomal

Created: 16 Jan 2019, 1:08 p.m.

Initial gene list and info collated by Ian Berry Leeds Genetics Laboratory November 2018 on behalf of the GMS Respiratory specialist test group. Gene Symbol submitted: ACVR2B; Suggested initial gene rating: Green; Evidence for inclusion: OMIM PCD or Visceral heterotaxy gene; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given

Created: 5 Dec 2018, 12:52 p.m.

Publications

• 9916847