NM_005902.4(SMAD3):c.1A>T (p.Met1Leu) AND Familial thoracic aortic aneurysm and aortic dissection

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 24, 2021
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:: RCV001231422.11

Allele description

NM_005902.4(SMAD3):c.1A>T (p.Met1Leu)

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.1A>T (p.Met1Leu)

HGVS:

NC_000015.10:g.67066155A>T
NG_011990.1:g.5299A>T
NM_005902.4:c.1A>TMANE SELECT
NP_005893.1:p.Met1Leu
NC_000015.9:g.67358493A>T
NM_005902.3:c.1A>T

Protein change:

M1L

Links:

dbSNP: rs1555405092

NCBI 1000 Genomes Browser:

rs1555405092

Molecular consequence:

NM_005902.4:c.1A>T - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_005902.4:c.1A>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001403942	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 24, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 29907982, 33125268, 29543232, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001403942

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 24, 2021)

germline

clinical testing

PubMed (4)
[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

Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders.

Overwater E, Marsili L, Baars MJH, Baas AF, van de Beek I, Dulfer E, van Hagen JM, Hilhorst-Hofstee Y, Kempers M, Krapels IP, Menke LA, Verhagen JMA, Yeung KK, Zwijnenburg PJG, Groenink M, van Rijn P, Weiss MM, Voorhoeve E, van Tintelen JP, Houweling AC, Maugeri A.

Hum Mutat. 2018 Sep;39(9):1173-1192. doi: 10.1002/humu.23565. Epub 2018 Jul 12.

PubMed [citation]

PMID:: 29907982
PMCID:: PMC6175145

Spontaneous Coronary Artery Dissection: Insights on Rare Genetic Variation From Genome Sequencing.

Carss KJ, Baranowska AA, Armisen J, Webb TR, Hamby SE, Premawardhana D, Al-Hussaini A, Wood A, Wang Q, Deevi SVV, Vitsios D, Lewis SH, Kotecha D, Bouatia-Naji N, Hesselson S, Iismaa SE, Tarr I, McGrath-Cadell L, Muller DW, Dunwoodie SL, Fatkin D, Graham RM, et al.

Circ Genom Precis Med. 2020 Dec;13(6):e003030. doi: 10.1161/CIRCGEN.120.003030. Epub 2020 Oct 30.

PubMed [citation]

PMID:: 33125268
PMCID:: PMC7748045

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001403942.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant has been observed in individuals affected with thoracic aortic aneurysm and/or dissection or arterial dissection (PMID: 29907982, 33125268 , Invitae). For these reasons, this allele has been classified as Pathogenic. This variant disrupts the initiator methionine in SMAD3. If translation initiates from the next in-frame methionine, the SMAD3 protein would no longer include the region containing the p.Arg93 amino acid residue. Other variant(s) that disrupt this residue have been observed in individuals with SMAD3-related conditions (PMID: 29543232, Invitae), which suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change affects the initiator methionine of the SMAD3 mRNA. The next in-frame methionine is located at codon 106.

#	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 1, 2024

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