NM_005902.4(SMAD3):c.1118G>A (p.Arg373His) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 5, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000469242.12

Allele description [Variation Report for NM_005902.4(SMAD3):c.1118G>A (p.Arg373His)]

NM_005902.4(SMAD3):c.1118G>A (p.Arg373His)

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.1118G>A (p.Arg373His)

HGVS:

NC_000015.10:g.67187473G>A
NG_011990.1:g.126617G>A
NM_001145102.2:c.803G>A
NM_001145103.2:c.986G>A
NM_001145104.2:c.533G>A
NM_005902.4:c.1118G>AMANE SELECT
NP_001138574.1:p.Arg268His
NP_001138575.1:p.Arg329His
NP_001138576.1:p.Arg178His
NP_005893.1:p.Arg373His
NC_000015.9:g.67479811G>A
NM_005902.3:c.1118G>A
p.Arg373His

Protein change:

R178H

Links:

dbSNP: rs1060500766

NCBI 1000 Genomes Browser:

rs1060500766

Molecular consequence:

NM_001145102.2:c.803G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001145103.2:c.986G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001145104.2:c.533G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005902.4:c.1118G>A - 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

Recent activity

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Mus musculus surfactant associated protein A1 (Sftpa1), mRNA
Mus musculus surfactant associated protein A1 (Sftpa1), mRNA
gi|31560851|ref|NM_023134.3|

Nucleotide
CVA-1_407L [Paramecium bursaria Chlorella virus CVA-1]
CVA-1_407L [Paramecium bursaria Chlorella virus CVA-1]
Gene ID:41900403

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000543852	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 5, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 25944730, 16828225, 30661052, 28492532
SCV002751808	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Nov 15, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16828225, 25944730, 30661052, 30739908, 31915033 Citation Link,
SCV003838411	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 14, 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

SCV000543852

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 5, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002751808

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Nov 15, 2021)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV003838411

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 14, 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

Genetic alterations of the TGF-beta signaling pathway in colorectal cancer cell lines: a novel mutation in Smad3 associated with the inactivation of TGF-beta-induced transcriptional activation.

Ku JL, Park SH, Yoon KA, Shin YK, Kim KH, Choi JS, Kang HC, Kim IJ, Han IO, Park JG.

Cancer Lett. 2007 Mar 18;247(2):283-92. Epub 2006 Jul 7.

PubMed [citation]

PMID:: 16828225

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000543852.7

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 373 of the SMAD3 protein (p.Arg373His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with SMAD3-related conditions (PMID: 25944730, 30661052; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 405561). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SMAD3 function (PMID: 16828225). This variant disrupts the p.Arg373 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been observed in individuals with SMAD3-related conditions (PMID: 30661052; Invitae), which suggests that this may be a clinically significant amino acid residue. 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

From Ambry Genetics, SCV002751808.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.R373H variant (also known as c.1118G>A), located in coding exon 8 of the SMAD3 gene, results from a G to A substitution at nucleotide position 1118. The arginine at codon 373 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals with thoracic aortic aneurysm, including one individual with additional concerns for a connective tissue disorder (Wooderchak-Donahue W et al. Am J Med Genet A, 2015 Aug;167A:1747-57; Arnaud P et al. Genet Med, 2019 09;21:2015-2024; Hostetler EM et al. J Med Genet, 2019 04;56:252-260; Yang H et al. Orphanet J Rare Dis, 2020 01;15:6; Ambry internal data). Additionally, this alteration was detected in a cancer cell line and suggested to possibly impact TGF-β signaling in in vitro assays, although the physiological relevance is unknown (Ku JL et al. Cancer Lett., 2007 Mar;247:283-92). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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

From CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario, SCV003838411.1

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

#	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: Oct 8, 2024

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