ClinVar Miner

Submissions for variant NM_005902.4(SMAD3):c.220C>T (p.Arg74Trp)

gnomAD frequency: 0.00001  dbSNP: rs1343295267
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000591279 SCV000708602 uncertain significance not provided 2017-05-17 criteria provided, single submitter clinical testing
Invitae RCV000697102 SCV000825693 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2023-08-17 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt SMAD3 function. ClinVar contains an entry for this variant (Variation ID: 502012). This missense change has been observed in individuals with SMAD3-related conditions (PMID: 29510914, 31096651; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 74 of the SMAD3 protein (p.Arg74Trp).
Color Diagnostics, LLC DBA Color Health RCV000697102 SCV001343376 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2023-10-12 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 74 in the MH1 DNA binding domain of the SMAD3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not alter SMAD3 protein expression levels, but does cause decreased cell survival and lack of downstream target gene expression (PMID: 34434896). This variant has been reported in two individuals affected with Loeys-Dietz syndrome (PMID: 31096651; communication with an external laboratory; ClinVar SCV000825693.5), in an individual affected with familial thoracic aortic dissection and aneurysm (PMID: 29510914), and in an individual affected with isolated thoracic aortic dissection and aneurysm (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg74Gln, is considered to be disease-causing (ClinVar variation ID: 623872), suggesting that arginine at this position is important for SMAD3 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
GeneDx RCV000591279 SCV001812607 uncertain significance not provided 2022-06-01 criteria provided, single submitter clinical testing Observed in an individual with TAAD and an individual with features of Loeys-Dietz syndrome type 3 (LDS3) who also harbored an additional cardiogenetic variant in the published literature (Hicks et al., 2018; Richter et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31096651, 29510914)
GenomeConnect, ClinGen RCV000844981 SCV000986808 not provided SMAD3-Related Disorder no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 10/21/2015 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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