NM_005902.4(SMAD3):c.721A>C (p.Asn241His) 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:: Jul 29, 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:: RCV002297188.3

Allele description

NM_005902.4(SMAD3):c.721A>C (p.Asn241His)

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.721A>C (p.Asn241His)

HGVS:

NC_000015.10:g.67181303A>C
NG_011990.2:g.120703A>C
NM_001145102.2:c.406A>C
NM_001145103.2:c.589A>C
NM_001145104.2:c.136A>C
NM_001407011.1:c.721A>C
NM_001407012.1:c.589A>C
NM_001407013.1:c.721A>C
NM_001407014.1:c.574A>C
NM_001407015.1:c.274A>C
NM_001407016.1:c.406A>C
NM_001407017.1:c.136A>C
NM_005902.4:c.721A>CMANE SELECT
NP_001138574.1:p.Asn136His
NP_001138575.1:p.Asn197His
NP_001138576.1:p.Asn46His
NP_001393940.1:p.Asn241His
NP_001393941.1:p.Asn197His
NP_001393942.1:p.Asn241His
NP_001393943.1:p.Asn192His
NP_001393944.1:p.Asn92His
NP_001393945.1:p.Asn136His
NP_001393946.1:p.Asn46His
NP_005893.1:p.Asn241His
NC_000015.9:g.67473641A>C
NG_011990.1:g.120447A>C

Protein change:

N136H

Molecular consequence:

NM_001145102.2:c.406A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001145103.2:c.589A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001145104.2:c.136A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407011.1:c.721A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407012.1:c.589A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407013.1:c.721A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407014.1:c.574A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407015.1:c.274A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407016.1:c.406A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001407017.1:c.136A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_005902.4:c.721A>C - 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
SCV002593109	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 29, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002593109

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 29, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

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, SCV002593109.3

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

Description

This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 241 of the SMAD3 protein (p.Asn241His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMAD3-related conditions. 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. 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.

#	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 20, 2024

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