NM_005902.4(SMAD3):c.445_455del (p.Glu149fs) AND Aneurysm-osteoarthritis syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 18, 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:: RCV001802457.7

Allele description [Variation Report for NM_005902.4(SMAD3):c.445_455del (p.Glu149fs)]

NM_005902.4(SMAD3):c.445_455del (p.Glu149fs)

Gene:

SMAD3:SMAD family member 3 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

15q22.33

Genomic location:

Preferred name:

NM_005902.4(SMAD3):c.445_455del (p.Glu149fs)

HGVS:

NC_000015.10:g.67165297_67165307del
NC_000015.9:g.67457633_67457643del
NG_011990.1:g.104441_104451del
NM_001145102.2:c.130_140del
NM_001145103.2:c.313_323del
NM_005902.4:c.445_455delMANE SELECT
NP_001138574.1:p.Glu44fs
NP_001138575.1:p.Glu105fs
NP_005893.1:p.Glu149fs
NC_000015.9:g.67457633_67457643del
NC_000015.9:g.67457635_67457645del
NC_000015.9:g.67457635_67457645delGAGTTCCCCCC

Protein change:

E105fs

Links:

dbSNP: rs2140294805

NCBI 1000 Genomes Browser:

rs2140294805

Molecular consequence:

NM_001145102.2:c.130_140del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001145103.2:c.313_323del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_005902.4:c.445_455del - frameshift variant - [Sequence Ontology: SO:0001589]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002048540	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Likely pathogenic (Sep 18, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002048540

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2021)

Likely pathogenic
(Sep 18, 2021)

germline

clinical testing

Citation Link

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

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002048540.1

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

Description

The SMAD3 c.445_455del, p.Glu149ThrfsTer13 variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 11 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in individuals with Loeys-Dietz syndrome and thoracic aortic disorder and are considered pathogenic (Hostetler 2019, Schepers 2018). Based on available information, this variant is considered to be likely pathogenic. References: Hostetler EM et al. SMAD3 pathogenic variants: risk for thoracic aortic disease and associated complications from the Montalcino Aortic Consortium. J Med Genet. 2019 Apr;56(4):252-260. PMID: 30661052. Schepers D et al. A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. Hum Mutat. 2018 May;39(5):621-634. PMID: 29392890.

#	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 29, 2024

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