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NM_005902.4(SMAD3):c.1118G>A (p.Arg373His) AND Aneurysm-osteoarthritis syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Mar 16, 2019
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:
RCV001001936.9

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:
Aneurysm-osteoarthritis syndrome
Synonyms:
ANEURYSMS-OSTEOARTHRITIS SYNDROME; LOEYS-DIETZ SYNDROME WITH OSTEOARTHRITIS; Loeys-Dietz syndrome 3; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0013426; MedGen: C3151087; Orphanet: 284984; OMIM: 613795

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001159707ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)		Uncertain significance
(Mar 16, 2019) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001159707.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The SMAD3 c.1118G>A; p.Arg373His variant (rs1060500766) is reported in the literature in a single individual affected with aortic dilation/dissection (Wooderchak-Donahue 2015). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported in ClinVar (Variation ID: 405561). The arginine at codon 373 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In cultured cells, this variant exhibits mildly reduced transcriptional activation activity and altered localization in response to TGF-beta treatment (Ku 2007), although it is not certain whether these properties are physiologically relevant. Due to limited information, the clinical significance of the p.Arg373His variant is uncertain at this time. References: Ku JL et al. 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. Cancer Lett. 2007 Mar 18;247(2):283-92. Wooderchak-Donahue W et al. Clinical utility of a next generation sequencing panel assay for Marfan and Marfan-like syndromes featuring aortopathy. Am J Med Genet A. 2015 Aug;167A(8):1747-57.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 8, 2024