NM_005902.4(SMAD3):c.1153dup (p.Arg385fs) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 5, 2022
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:: RCV000707067.5

Allele description [Variation Report for NM_005902.4(SMAD3):c.1153dup (p.Arg385fs)]

NM_005902.4(SMAD3):c.1153dup (p.Arg385fs)

Gene:

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

Variant type:

Duplication

Cytogenetic location:

15q22.33

Genomic location:

Preferred name:

NM_005902.4(SMAD3):c.1153dup (p.Arg385fs)

HGVS:

NC_000015.10:g.67187508dup
NG_011990.1:g.126652dup
NM_001145102.2:c.838dup
NM_001145103.2:c.1021dup
NM_001145104.2:c.568dup
NM_005902.4:c.1153dupMANE SELECT
NP_001138574.1:p.Arg280fs
NP_001138575.1:p.Arg341fs
NP_001138576.1:p.Arg190fs
NP_005893.1:p.Arg385fs
NC_000015.9:g.67479845_67479846insA
NC_000015.9:g.67479846dup
NM_005902.3:c.1153dupA

Protein change:

R190fs

Links:

dbSNP: rs1567003613

NCBI 1000 Genomes Browser:

rs1567003613

Molecular consequence:

NM_001145102.2:c.838dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001145103.2:c.1021dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001145104.2:c.568dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_005902.4:c.1153dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000836147	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 5, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30661052, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000836147

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 5, 2022)

germline

clinical testing

PubMed (2)
[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

SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium.

Hostetler EM, Regalado ES, Guo DC, Hanna N, Arnaud P, Muiño-Mosquera L, Callewaert BL, Lee K, Leal SM, Wallace SE, Rideout AL, Dyack S, Aatre RD, Boileau C, De Backer J, Jondeau G, Milewicz DM.

J Med Genet. 2019 Apr;56(4):252-260. doi: 10.1136/jmedgenet-2018-105583. Epub 2019 Jan 19.

PubMed [citation]

PMID:: 30661052

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000836147.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SMAD3 protein in which other variant(s) (p.Trp406*) have been determined to be pathogenic (PMID: 30661052; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 582880). 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). This sequence change creates a premature translational stop signal (p.Arg385Lysfs*13) in the SMAD3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 41 amino acid(s) of the SMAD3 protein.

#	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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