NM_005902.4(SMAD3):c.484G>A (p.Glu162Lys) AND Aneurysm-osteoarthritis syndrome

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 4, 2023
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:: RCV004013250.2

Allele description [Variation Report for NM_005902.4(SMAD3):c.484G>A (p.Glu162Lys)]

NM_005902.4(SMAD3):c.484G>A (p.Glu162Lys)

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.484G>A (p.Glu162Lys)

HGVS:

NC_000015.10:g.67165336G>A
NG_011990.1:g.104480G>A
NG_011990.2:g.104736G>A
NM_001145102.2:c.169G>A
NM_001145103.2:c.352G>A
NM_001407011.1:c.484G>A
NM_001407012.1:c.400+248G>A
NM_001407013.1:c.484G>A
NM_001407014.1:c.337G>A
NM_001407015.1:c.85+248G>A
NM_001407016.1:c.169G>A
NM_005902.4:c.484G>AMANE SELECT
NP_001138574.1:p.Glu57Lys
NP_001138575.1:p.Glu118Lys
NP_001393940.1:p.Glu162Lys
NP_001393942.1:p.Glu162Lys
NP_001393943.1:p.Glu113Lys
NP_001393945.1:p.Glu57Lys
NP_005893.1:p.Glu162Lys
NC_000015.9:g.67457674G>A

Protein change:

E113K

Molecular consequence:

NM_001407012.1:c.400+248G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001407015.1:c.85+248G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001145102.2:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001145103.2:c.352G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407011.1:c.484G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407013.1:c.484G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407014.1:c.337G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407016.1:c.169G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005902.4:c.484G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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PREDICTED: Homo sapiens centromere protein U (CENPU), transcript variant X1, mRN...
PREDICTED: Homo sapiens centromere protein U (CENPU), transcript variant X1, mRNA
gi|2462598864|ref|XM_054350827.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004824797	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (May 4, 2023)	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

SCV004824797

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(May 4, 2023)

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	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004824797.1

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

Description

This missense variant replaces glutamic acid with lysine at codon 162 of the SMAD3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SMAD3-related disorders in the literature. This variant has been identified in 1/251442 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 1, 2024

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