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Mendeliome

Gene: SMAD5

Green List (high evidence)

SMAD5 (SMAD family member 5)
EnsemblGeneIds (GRCh38): ENSG00000113658
EnsemblGeneIds (GRCh37): ENSG00000113658
OMIM: 603110, Gene2Phenotype
SMAD5 is in 3 panels

1 review

Sarah Milton (Other)

Green List (high evidence)

SMAD5 encodes a transcriptional regulator that functions within the TGF-b signalling cascade. Animal studies show this protein is crucial for dorsoventral patterning, left/right asymmetry, cardiac looping.

7 affected individuals from 6 families described in PMID: 40619738 with congenital heart disease (ASD, VSD, hypoplastic left heart). 4 cases had de novo variants in SMAD5 with some cases having inheritance from presumably unaffected parents (however parents weren't formally assessed). All variants absent from gnomAD v4.

Supportive functional studies with transfection of variants into HEK293T cells showing reduced SMAD5 levels and luciferase promoter assay showing reduced promoter activity of downstream targets with rescue upon introduction of WT SMAD5. LOF mechanism proposed. Variants were missense/nonsense/frameshift/large del.

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.
Sources: Literature
Created: 5 Aug 2025, 6:36 a.m. | Last Modified: 5 Aug 2025, 6:37 a.m.
Panel Version: 1.2806

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Congenital heart disease, MONDO:0005453, SMAD5-related

Publications

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
Phenotypes
  • Congenital heart disease, MONDO:0005453, SMAD5-related
OMIM
603110
Clinvar variants
Variants in SMAD5
Penetrance
Incomplete
Publications
Panels with this gene

History Filter Activity

5 Aug 2025, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: smad5 has been classified as Green List (High Evidence).

5 Aug 2025, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: smad5 has been classified as Green List (High Evidence).

5 Aug 2025, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Sarah Milton (Other)

gene: SMAD5 was added gene: SMAD5 was added to Mendeliome. Sources: Literature Mode of inheritance for gene: SMAD5 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SMAD5 were set to PMID: 40619738 Phenotypes for gene: SMAD5 were set to Congenital heart disease, MONDO:0005453, SMAD5-related Penetrance for gene: SMAD5 were set to Incomplete Review for gene: SMAD5 was set to GREEN