NM_005902.4(SMAD3):c.934G>A (p.Ala312Thr) AND Aneurysm-osteoarthritis syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 31, 2023
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:: RCV002485303.3

Allele description [Variation Report for NM_005902.4(SMAD3):c.934G>A (p.Ala312Thr)]

NM_005902.4(SMAD3):c.934G>A (p.Ala312Thr)

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.934G>A (p.Ala312Thr)

Other names:

p.A312T:GCT>ACT

HGVS:

NC_000015.10:g.67184789G>A
NG_011990.1:g.123933G>A
NM_001145102.2:c.619G>A
NM_001145103.2:c.802G>A
NM_001145104.2:c.349G>A
NM_005902.4:c.934G>AMANE SELECT
NP_001138574.1:p.Ala207Thr
NP_001138575.1:p.Ala268Thr
NP_001138576.1:p.Ala117Thr
NP_005893.1:p.Ala312Thr
NC_000015.9:g.67477127G>A
NM_005902.3:c.934G>A

Protein change:

A117T

Links:

dbSNP: rs750756638

NCBI 1000 Genomes Browser:

rs750756638

Molecular consequence:

NM_001145102.2:c.619G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001145103.2:c.802G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001145104.2:c.349G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_005902.4:c.934G>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002777275	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 1, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004815401	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (May 31, 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

SCV002777275

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 1, 2021)

unknown

clinical testing

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

SCV004815401

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(May 31, 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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
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 Fulgent Genetics, Fulgent Genetics, SCV002777275.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004815401.1

#	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 alanine with threonine at codon 312 of the SMAD3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 cardiovascular disorders in the literature. This variant has been identified in 1/251456 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 29, 2024

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