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SMAD6 Gene Curation

SMAD6 Gene Curation

Owned by Andrea Oza
Last updated: 2025-03-25
5 min read

Gene-disease assertions not curated here (add link or write note):

I began curating this gene due to no ClinGen curation and conflicts in GenCC, but then reached out to Marina to ask about reportability. For some reason the curation was not on the ClinGen website https://broadinstitute.slack.com/archives/C07SV9X3EKA/p1742913326278099

Per Marina, this gene has been curated as DEFINITIVE by the craniofacial malformations GCEP for “SMAD6-related disorder”. They lumped Aortic valve disease, craniosynostosis, and radioulnar synostosis:

SMAD6 was first reported in relation to autosomal dominant [SMAD6-related disorder] in  2016 (Timberlake et al., PMID: 27606499). [SMAD6-related disorder] is the presentation of Craniosynostosis with congenital heart defects and/or radioulnar synostosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in [molecular mechanism and inheritance pattern. Variants in SMAD6 causing Aortic valve disease, craniosynostosis, and radioulnar synostosis were located throughout the gene. Reports have also shown various syndromic presentations of SMAD6 variants. Therefore, the  following disease entities have been lumped into one disease entity, Aortic Valve Disease 2 (OMIM:614823), Craniosynostosis 7 (OMIM:617439), and Radioulnar Synostosis (OMIM:179300). 28 variants (missense, nonsense, and frameshift) that have been reported in 28 probands in 3 publications (PMIDs: 34953066, 32499606, 27606499) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by animal models and expression studies (PMIDs: 21681813, 10655064). SMAD6 was found to be expressed in developing cardiac tissue and bones, and mice deficient in SMAD6 were found to exhibit phenotypes similar to Aortic Valve Disorder and Craniosynostosis. In summary, SMAD6 is definitively associated with autosomal dominant [SMAD6-related disorder]. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Craniofacial Malformations GCEP on the meeting date 06/15/2023 (SOP Version 9).

 

PMID: 28991257 - Congenital heart defects, in supplement - cohort of trios. Unclear if these are all de novo.

Per table S9 p.G136fs is de novo in patient 1-10568 with CTD. The remaining variants below were transmitted per table S7

c.263dup

p.(Arg91Glufs*30)

LVO

c.409dup

p.(Ala137Glyfs*166)

CTD

c.577G>T

p.(Glu193*)

LVO

c.933del

p.(Ala312Leufs*227)

CTD

c.1059del

p.(Val354Serfs*185)

LVO

c.1074C>A

p.(Tyr358*)

CTD

c.1156A>T

p.(Lys386*)

Other

c.1302C>G

p.(Tyr434*)

TGA

c.1422del

p.(Cys475Alafs*64)

CTD

Disease

Aortic valve disease 2

Disease

Aortic valve disease 2

Inheritance

Autosomal dominant

Prevalence

Orphanet

Medline Plus Genetics

 

Source:

Rapid or full curation?

Rapid
Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - none. GenCC - Moderate by Ambry and Limited by Invitae. Limited by BabySeq

PRECURATION FROM CONGENITAL HEART DISEASE GCEP https://docs.google.com/presentation/d/1u52Aqy6x5dMUWmAsNsmXTGy19KCKPGjtHkpYWU14dSk/edit#slide=id.g2429de2f92b_0_7

Clinical Validity Scoring Notes and points

Bicuspid aortic valve is the most common congenital heart defect, 1-2% of the population. SCORED AS COMMON DISEASE

Gene is not LOF constrained in gnomAD

 

PMID: 36414630 - Review

  • Variants in SMAD6 associated with congenital heart defects, craniosynostosis, and radioulnar synostosis.

    image-20250324-212248.png

PMID: 30796334

  • Deletion of the complete coding region of SMAD6 and exon 1 of SMAD3 (not scoring due to overlap with another gene)

  • Family 2 and 3 has 2 different variants; did not score

  • c.42G>A p.W14* - 6 alleles total gnomAD v4. Reported in family 4 from cohort of patients with thoracic aortic aneurysm. Per table 2 patient with bicuspid aortic valve and TAA. 1 POINT

  • His265Profs*274 (extension variant) - reported in family 5 with bicuspid aortic valve and TAA, segregated in affected family member with thoracic-abdominal diffuse aneurysm. 0.5 POINT

  • Gly204Ala (absent) in patient 6-II:1 with BAV and ascending aorta aneursym. 0.1 POINT

PMID: 28974934

  • Large (441 patients)cohort of bicuspid aortic valve / thoracic aortic aneurysm; Variant burden found to be increased in the cohort compared to ExAC data (p=0.002)

  • In the supplement:

    • c.74_79del p.Ser27_Gly28del - too frequent in gnomad, 822 alleles

    • c.455_461del p.Pro152Profs*27 - 2 alleles gnomAD v4 (NMD +, 1 POINT)

    • c.715G>A p.Val239Met - 227 alleles, no evidence

    • c.726del p.Lys242Asnfs*300 - 2 alleles gnomAD v4, extension variant 0.5 POINT

    • c.770C>T p.Pro257Leu - 5 alleles gnomad v4

    • c.812G>A p.Gly271Glu - 1 allele 0.1 POINT

    • c.837C>A p.Tyr279* - 1 allele, NMD+ 1 POINT

    • c.864C>G p.Tyr288* - 1 allele, NMD+ 1 POINT

    • c.1216G>T p.Gly406Cys - 2 alleles 0.1 POINT

    • c.1224C>G p.His408Gln - 3 alleles 0.1 POINT

    • c.389C>T p.Ser130Leu - 2 alleles 0.1 POINT

5.5

PMID: 22275001 -

  • 90 unrelated patients with congenital cardiovascular malformations.

  • c.1244C>T p.P415L - patient with aortic stenosis with bicuspid aortic valve - 18 alleles gnomAD. Did not score.

  • c.1451G>T p.C484F - patient with bicuspid valve and coarctation of the aorta. - 4 alleles gnomAD v4. 0.1 POINT + 0.5 POINT = 0.6 POINT

  • Ala325Thr - patient with mitral valve regurgitation

  • Two SMAD6 variants (p.C484F and p.P415L) had significantly (P < 0.05) lower activity than wild-type SMAD6 in inhibiting BMP signaling in a transcriptional reporter assay

PMID: 30848080

  • c.1168_1173dup; p.Gly390_Ile391dup - absent gnomAD V4, reported in a patient w/ BAV, and dilation of ascending aorta, severe calcification of the aortic valve. In vitro functional study of the p.Gly390_ Ile391dup variant revealed impaired inhibition of BMP signaling and BMP‐induced alkaline phosphatase activity. 0.5 + 0.5 functional = 1 POINT

PMID: 35910219

  • SMAD6 listed in table 3, but noted to also have del 15q11.2. No Evidence.

PMID: 30293987

  • c.86del p.Gly29Alafs*35 in a patient with a functional single ventricle per table 2 - congenital heart defect.

  • 32748548

PMID: 28991257

Experimental:

PMID: 10655064 - Madh6 -/- (Smad6 analog) mutant mice created by insertion of a LacZ reporter demonstrate cardiac septation defects and cardiac valve hyperplasia. Downgrading to 1 point given it is biallelic mice. 1 POINT ANIMAL MODEL

PMID: - SMAD6 is expressed in endothelial cells during cardiac cushion defects.

Clinical Validity Points Total

 

Source:

Clinical Validity Classification

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

 

Source:

Molecular Mechanism

Loss of function

Gain of function

Dominant negative

Unknown

Other

Loss of function / Gain of function / Dominant Negative

 

Penetrance

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

 

Source:

Age of Onset

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

 

Severity

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

 

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

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

 

Case ID, Curator name, Date, Jira ticket link

AO E3860819100 03/25/2025

 

 

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