NM_005902.4(SMAD3):c.1029C>G (p.Phe343Leu) AND Familial thoracic aortic aneurysm and aortic dissection

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

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Sep 15, 2020
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:: RCV001367316.5

Allele description

NM_005902.4(SMAD3):c.1029C>G (p.Phe343Leu)

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.1029C>G (p.Phe343Leu)

HGVS:

NC_000015.10:g.67187384C>G
NG_011990.1:g.126528C>G
NM_001145102.2:c.714C>G
NM_001145103.2:c.897C>G
NM_001145104.2:c.444C>G
NM_005902.4:c.1029C>GMANE SELECT
NP_001138574.1:p.Phe238Leu
NP_001138575.1:p.Phe299Leu
NP_001138576.1:p.Phe148Leu
NP_005893.1:p.Phe343Leu
NC_000015.9:g.67479722C>G

Protein change:

F148L

Links:

dbSNP: rs2140323430

NCBI 1000 Genomes Browser:

rs2140323430

Molecular consequence:

NM_001145102.2:c.714C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001145103.2:c.897C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001145104.2:c.444C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_005902.4:c.1029C>G - 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
SCV001563663	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 15, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31915033, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001563663

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 15, 2020)

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

Genetic profiling and cardiovascular phenotypic spectrum in a Chinese cohort of Loeys-Dietz syndrome patients.

Yang H, Ma Y, Luo M, Zhu G, Zhang Y, Li B, Shu C, Zhou Z.

Orphanet J Rare Dis. 2020 Jan 8;15(1):6. doi: 10.1186/s13023-019-1282-3.

PubMed [citation]

PMID:: 31915033
PMCID:: PMC6950884

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 Invitae, SCV001563663.3

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

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMAD3 protein function. This variant has been observed in individual(s) with clinical features of SMAD3-related disease (PMID: 31915033). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with leucine at codon 343 of the SMAD3 protein (p.Phe343Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine.

#	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: Mar 5, 2024

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