ClinVar Miner

Submissions for variant NM_005902.4(SMAD3):c.860G>A (p.Arg287Gln)

dbSNP: rs730880214
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197902 SCV000250762 pathogenic not provided 2022-01-24 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated that p.(R287Q) resulted in 44% and 20% lower SMAD3 expression in both kidney and liver respectively, compared to the control (Meier et al., 2020); 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: 28185953, 32100971, 30661052, 26221609, 31085000, 30679815, 24804794)
Center for Human Genetics, Inc, Center for Human Genetics, Inc RCV000660271 SCV000782295 pathogenic Connective tissue disorder 2016-11-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001198563 SCV001369552 likely pathogenic Aneurysm-osteoarthritis syndrome 2019-09-05 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PM5,PP3.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000197902 SCV001447568 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798527 SCV002043365 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2020-07-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001798527 SCV002246030 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2023-07-19 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 287 of the SMAD3 protein (p.Arg287Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with SMAD3-related conditions (PMID: 24804794, 30661052, 31085000). ClinVar contains an entry for this variant (Variation ID: 180524). 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. This variant disrupts the p.Arg287 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21217753, 25644172; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV000157501 SCV000207246 uncertain significance Loeys-Dietz syndrome 2014-08-26 no assertion criteria provided clinical testing

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