Submissions for variant NM_005902.4(SMAD3):c.802C>T (p.Arg268Cys)

dbSNP: rs794727798

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179456	SCV000231708	pathogenic	not provided	2015-10-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000179456	SCV000250758	likely pathogenic	not provided	2024-12-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published in vitro functional studies suggest decreased transcriptional activity; however, it is unknown whether these findings replicate in vivo effect (PMID: 10092624, 23139211); 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: 23139211, 25944730, 21949838, 29907982, 32123317, 38538566, 34663891, 10092624)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852232	SCV002131323	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 268 of the SMAD3 protein (p.Arg268Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of SMAD3-related conditions (PMID: 29907982; Invitae). ClinVar contains an entry for this variant (Variation ID: 198187). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SMAD3 function (PMID: 10092624). This variant disrupts the p.Arg268 amino acid residue in SMAD3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25944730, 26854089; 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000179456	SCV005414288	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing	PP2, PP3, PM1, PM2, PM5, PS3, PS4_moderate
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000179456	SCV001808492	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000179456	SCV001964192	likely pathogenic	not provided		no assertion criteria provided	clinical testing