NM_005902.4(SMAD3):c.5C>A (p.Ser2Ter) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 22, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001218505.4

Allele description [Variation Report for NM_005902.4(SMAD3):c.5C>A (p.Ser2Ter)]

NM_005902.4(SMAD3):c.5C>A (p.Ser2Ter)

Genes:

LOC130057352:ATAC-STARR-seq lymphoblastoid silent region 6574 [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.5C>A (p.Ser2Ter)

HGVS:

NC_000015.10:g.67066159C>A
NG_011990.1:g.5303C>A
NM_005902.4:c.5C>AMANE SELECT
NP_005893.1:p.Ser2Ter
NC_000015.9:g.67358497C>A
NM_005902.3:c.5C>A

Protein change:

S2*

Links:

dbSNP: rs1006530719

NCBI 1000 Genomes Browser:

rs1006530719

Molecular consequence:

NM_005902.4:c.5C>A - 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
SCV001390389	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 22, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21778426, 24804794, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001390389

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 22, 2023)

germline

clinical testing

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

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

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

Early-onset osteoarthritis, Charcot-Marie-Tooth like neuropathy, autoimmune features, multiple arterial aneurysms and dissections: an unrecognized and life threatening condition.

Aubart M, Gobert D, Aubart-Cohen F, Detaint D, Hanna N, d'Indya H, Lequintrec JS, Renard P, Vigneron AM, Dieudé P, Laissy JP, Koch P, Muti C, Roume J, Cusin V, Grandchamp B, Gouya L, LeGuern E, Papo T, Boileau C, Jondeau G.

PLoS One. 2014;9(5):e96387. doi: 10.1371/journal.pone.0096387.

PubMed [citation]

PMID:: 24804794
PMCID:: PMC4012990

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001390389.5

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

Description

This sequence change creates a premature translational stop signal (p.Ser2*) in the SMAD3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMAD3 are known to be pathogenic (PMID: 21778426, 24804794). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 451689). This variant has not been reported in the literature in individuals affected with SMAD3-related conditions. This variant is not present in population databases (gnomAD no frequency).

#	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: Feb 28, 2024

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