1. Panels
  2. Fetal anomalies
  3. SMAD5
Genes in panel
Prev Next

Fetal anomalies

Gene: SMAD5

Amber List (moderate evidence)
SMAD5 (SMAD family member 5)
EnsemblGeneIds (GRCh38): ENSG00000113658
EnsemblGeneIds (GRCh37): ENSG00000113658
OMIM: 603110, Gene2Phenotype
SMAD5 is in 2 panels

3 reviews

Ludmila Volozonoka (Children's Clinical University Hospital)

Green List (high evidence)

PMID: 40619738: SMAD5 variants were identified in 7 individuals from 6 unrelated families, all with CHD. Six individuals had predominantly isolated CHD, while one individual (F1.3) had a multisystem phenotype.
Six unique SMAD5 variants were identified: 3 missense variants (p.Thr430Ile, p.Val78Phe, p.Asn361Asp), 2 truncating/LOF variants (p.Ala402Glufs13 and p.Glu261Ter) and 1 copy-number deletion encompassing SMAD5. Four variants were de novo (p.Thr430Ile, p.Val78Phe, p.Asn361Asp and the 5q31.1-q31.2 deletion); p.Ala402Glufs13 was inherited by two affected brothers from a mother who was presumed asymptomatic but was not formally assessed. The authors propose haploinsufficiency as the main mechanism in five of six families, whereas p.Thr430Ile showed functional evidence consistent with a dominant-negative mechanism and was associated with the only multisystem phenotype.

PMID: 39631055: Two unrelated patients with pulmonary arterial hypertension (PAH) carried heterozygous SMAD5 missense variants. The second patient carried p.Trp93Arg and had CHD-associated PAH following surgically repaired VSD; her father also had VSD but was not reported to have PAH.

PMID: 42481704: Two heterozygous SMAD5 variants were identified in association with PDA. The first, p.Lys82*, was identified in a five-generation family with PDA and segregated with the PDA phenotype. The second, p.Arg70Ile, was identified in one sporadic PDA patient among 174 CHD index cases and was reported as de novo.
Created: 22 Sep 2026, 11:11 a.m. | Last Modified: 22 Sep 2026, 11:11 a.m.
Panel Version: 8.7

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
congenitad heart defect; patent ductus arteriosus; ventricular septal defect; hypoplastic left heart

Publications

Created: 22 Sep 2026, 11:11 a.m.
Last Modified: 22 Sep 2026, 11:11 a.m.
Panel version: 8.7

Arina Puzriakova (Genomics England Curator)

This gene and phenotype were reviewed during meetings between November 2025 & January 2026. The meetings included representatives of the Central & South and North Thames R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Stephanie Allen, Elizabeth Young and Sarah Graham (Central & South GLH), Natalie Chandler and Elizabeth Scotchman (North Thames GLH), and Tazeen Ashraf, Anna De Burca, Natalie Canham, Samantha Doyle, Alice Gardham, Victoria Harrison, Tessa Homfray, Esther Kinning, and Soo-Mi Park (R21 Clinical Oversight Group).
Created: 10 Mar 2026, 11:35 a.m. | Last Modified: 10 Mar 2026, 11:35 a.m.
Panel Version: 6.148
Created: 10 Mar 2026, 11:35 a.m.
Last Modified: 10 Mar 2026, 11:35 a.m.
Panel version: 6.148

Natalie Chandler (North Thames GLH)

I don't know

Not reviewed in UK panel app, green Aus panel app. 4061973 7 affected individuals from 6 families, 4 de novo rest assumed inherited unaffected parents. Congenital heart disease (ASD, VSD, hypoplastic left heart). One individual presented with a more severe multi system phenotype including tetralogy of fallot, craniofacial/urogenital/renal/limb/vertebral anomalies with a variant that was proposed to act in a dominant negative manner. NM_005903.7(SMAD5):c.1289C>T|p.Thr430Ile. Functional studies performed supported this proposed mechanism. Amber - only severe case may qualify for R21?
Created: 10 Mar 2026, 11:27 a.m. | Last Modified: 10 Mar 2026, 11:27 a.m.
Panel Version: 6.147

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
congenital heart disease

Publications

Created: 10 Mar 2026, 11:27 a.m.
Last Modified: 10 Mar 2026, 11:27 a.m.
Panel version: 6.147

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
Phenotypes
  • congenital heart disease
OMIM
603110
Clinvar variants
Variants in SMAD5
Penetrance
None
Panels with this gene

History Filter Activity

10 Mar 2026, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Added phenotypes congenital heart disease for gene: SMAD5

9 Mar 2026, Gel status: 2

Created, Added New Source, Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

gene: SMAD5 was added gene: SMAD5 was added to Fetal anomalies. Sources: Expert Review Amber Mode of inheritance for gene: SMAD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted