Submissions for variant NM_005902.4(SMAD3):c.508A>G (p.Ile170Val)

gnomAD frequency: 0.03414  dbSNP: rs35874463

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000128164	SCV000171756	benign	not specified	2012-11-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000128164	SCV000269836	benign	not specified	2013-04-04	criteria provided, single submitter	clinical testing	Ile170Val in exon 3 of SMAD3: This variant is not expected to have clinical sign ificance because it has been identified in 5.5% (470/8598) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs35874463).
PreventionGenetics, part of Exact Sciences	RCV000128164	SCV000311292	benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000246765	SCV000317307	benign	Familial thoracic aortic aneurysm and aortic dissection	2014-11-25	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000128164	SCV000335030	benign	not specified	2015-09-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000405224	SCV000393485	likely benign	Loeys-Dietz syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000755392	SCV000393486	benign	Aneurysm-osteoarthritis syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000246765	SCV000556220	benign	Familial thoracic aortic aneurysm and aortic dissection	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000755392	SCV000605217	benign	Aneurysm-osteoarthritis syndrome	2018-09-05	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000128164	SCV000740517	benign	not specified	2015-11-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000246765	SCV000910556	benign	Familial thoracic aortic aneurysm and aortic dissection	2018-03-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000128164	SCV001362469	benign	not specified	2019-09-23	criteria provided, single submitter	clinical testing	Variant summary: SMAD3 c.508A>G (p.Ile170Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.04 in 251386 control chromosomes in the gnomAD database, including 275 homozygotes. The observed variant frequency is approximately 1056 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMAD3 causing Aortopathy phenotype (3.8e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.508A>G in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=5)/likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000246765	SCV002043358	benign	Familial thoracic aortic aneurysm and aortic dissection	2019-05-09	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277275	SCV002566098	benign	Ehlers-Danlos syndrome	2022-07-07	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573465	SCV001799381	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000128164	SCV001808640	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000128164	SCV001927198	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000128164	SCV001952169	benign	not specified		no assertion criteria provided	clinical testing
Cohesion Phenomics	RCV003148653	SCV003836802	benign	Thoracic aortic aneurysm	2022-09-23	no assertion criteria provided	clinical testing