ClinVar Miner

Submissions for variant NM_005902.4(SMAD3):c.870C>T (p.Ile290=)

gnomAD frequency: 0.01464  dbSNP: rs117185005
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000128165 SCV000171757 benign not specified 2012-11-02 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.
Preventiongenetics, part of Exact Sciences RCV000128165 SCV000311295 benign not specified criteria provided, single submitter clinical testing
Ambry Genetics RCV000251402 SCV000317351 benign Familial thoracic aortic aneurysm and aortic dissection 2015-03-06 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.
Illumina Laboratory Services, Illumina RCV000251402 SCV000393489 likely benign Familial thoracic aortic aneurysm and aortic dissection 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000362675 SCV000393490 likely benign Loeys-Dietz syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000251402 SCV000556217 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 RCV000755393 SCV000605216 benign Aneurysm-osteoarthritis syndrome 2023-11-30 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000251402 SCV000910588 benign Familial thoracic aortic aneurysm and aortic dissection 2018-03-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000128165 SCV001362470 benign not specified 2019-10-22 criteria provided, single submitter clinical testing Variant summary: SMAD3 c.870C>T (p.Ile290Ile) alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.016 in 246116 control chromosomes, predominantly at a frequency of 0.024 within the Non-Finnish European subpopulation in the gnomAD database, including 29 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 640 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 a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.870C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submissions (evaluation after 2014) cite the variant four times as benign and once as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002277276 SCV002566108 benign Ehlers-Danlos syndrome 2022-06-30 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000251402 SCV004239710 benign Familial thoracic aortic aneurysm and aortic dissection 2022-11-04 criteria provided, single submitter clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV001572817 SCV001797776 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000128165 SCV001809544 benign not specified no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000128165 SCV001932928 benign not specified no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000128165 SCV001970082 benign not specified no assertion criteria provided clinical testing

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