NM_005902.4(SMAD3):c.82G>T (p.Glu28Ter) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Feb 5, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000772179.9

Allele description [Variation Report for NM_005902.4(SMAD3):c.82G>T (p.Glu28Ter)]

NM_005902.4(SMAD3):c.82G>T (p.Glu28Ter)

Gene:

SMAD3:SMAD family member 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q22.33

Genomic location:

Preferred name:

NM_005902.4(SMAD3):c.82G>T (p.Glu28Ter)

Other names:

p.E28*:GAG>TAG

HGVS:

NC_000015.10:g.67066236G>T
NG_011990.1:g.5380G>T
NM_005902.4:c.82G>TMANE SELECT
NP_005893.1:p.Glu28Ter
NC_000015.9:g.67358574G>T
NM_005902.3:c.82G>T

Protein change:

E28*

Links:

dbSNP: rs863223750

NCBI 1000 Genomes Browser:

rs863223750

Molecular consequence:

NM_005902.4:c.82G>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:: Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:: MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000905296	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 3, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001402828	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 3, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21778426, 24804794, 28492532
SCV005024400	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Feb 5, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000905296

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 3, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001402828

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 3, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV005024400

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Feb 5, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms.

Regalado ES, Guo DC, Villamizar C, Avidan N, Gilchrist D, McGillivray B, Clarke L, Bernier F, Santos-Cortez RL, Leal SM, Bertoli-Avella AM, Shendure J, Rieder MJ, Nickerson DA; NHLBI GO Exome Sequencing Project., Milewicz DM.

Circ Res. 2011 Sep 2;109(6):680-6. doi: 10.1161/CIRCRESAHA.111.248161. Epub 2011 Jul 21.

PubMed [citation]

PMID:: 21778426
PMCID:: PMC4115811

See all PubMed Citations (5)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000905296.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Pathogenic variant based on current evidence: This variant changes 1 nucleotide in exon 1 of the SMAD3 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant is rare in the general population and has been identified in 0/277264 chromosomes by the Genome Aggregation Database (gnomAD). Loss of SMAD3 function is a known mechanism of disease for cardiovascular disorders. Based on available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001402828.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Loss-of-function variants in SMAD3 are known to be pathogenic (PMID: 21778426, 24804794). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with SMAD3-related conditions. ClinVar contains an entry for this variant (Variation ID: 213779). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Glu28*) in the SMAD3 gene. It is expected to result in an absent or disrupted protein product.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV005024400.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The p.E28* variant (also known as c.82G>T), located in coding exon 1 of the SMAD3 gene, results from a G to T substitution at nucleotide position 82. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. The predicted stop codon occurs in the 5’ end of theSMAD3 gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). Direct evidence for this alteration is unavailable, however premature termination codons are typically deleterious in nature. This alteration has been reported in a thoracic aortic aneurysm and dissection (TAAD) cohort (Hostetler EM et al. J Med Genet, 2019 Apr;56:252-260). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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