NM_005902.4(SMAD3):c.871+1G>A AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 3, 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:: RCV001869307.6

Allele description [Variation Report for NM_005902.4(SMAD3):c.871+1G>A]

NM_005902.4(SMAD3):c.871+1G>A

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.871+1G>A

HGVS:

NC_000015.10:g.67181454G>A
NG_011990.1:g.120598G>A
NG_011990.2:g.120854G>A
NM_001145102.2:c.556+1G>A
NM_001145103.2:c.739+1G>A
NM_001145104.2:c.286+1G>A
NM_001407011.1:c.871+1G>A
NM_001407012.1:c.739+1G>A
NM_001407013.1:c.871+1G>A
NM_001407014.1:c.724+1G>A
NM_001407015.1:c.424+1G>A
NM_001407016.1:c.556+1G>A
NM_001407017.1:c.286+1G>A
NM_005902.4:c.871+1G>AMANE SELECT
NC_000015.9:g.67473792G>A
NM_005902.3:c.871+1G>A

Links:

dbSNP: rs1595956832

NCBI 1000 Genomes Browser:

rs1595956832

Molecular consequence:

NM_001145102.2:c.556+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001145103.2:c.739+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001145104.2:c.286+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407011.1:c.871+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407012.1:c.739+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407013.1:c.871+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407014.1:c.724+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407015.1:c.424+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407016.1:c.556+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001407017.1:c.286+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_005902.4:c.871+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Functional consequence:

sequence_variant_affecting_splicing [Sequence Ontology: SO:1000071]

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
SCV002250822	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32597575, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002250822

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 3, 2023)

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

Identification of novel splice mutation in SMAD3 in two Cypriot families with nonsyndromic thoracic aortic aneurysm. Two case reports.

Keravnou A, Bashiardes E, Barberis V, Michailidou K, Soteriou M, Tanteles GA, Cariolou MA.

Mol Genet Genomic Med. 2020 Sep;8(9):e1378. doi: 10.1002/mgg3.1378. Epub 2020 Jun 29.

PubMed [citation]

PMID:: 32597575
PMCID:: PMC7507478

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, SCV002250822.3

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

Description

This sequence change affects a donor splice site in intron 6 of the SMAD3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 32597575). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 692110). Studies have shown that disruption of this splice site results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 32597575). For these reasons, this variant has been 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

Last Updated: Sep 29, 2024

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