ClinVar Miner

Submissions for variant NM_005902.4(SMAD3):c.1268G>C (p.Ser423Thr)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV004594823 SCV005086371 likely pathogenic Aneurysm-osteoarthritis syndrome 2024-09-20 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Loeys-Dietz syndrome 3 (MIM#613795). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical features of Loeys-Dietz syndrome associated with SMAD3 are variable, and the penetrance of aortic events generally increases with age (PMIDs: 20301312, 30661052). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to threonine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. At least three alternative amino acid changes at the same amino acid position, p.(Ser423Asn), p.(Ser423Arg) and p.(Ser423Gly), have been reported in individuals with SMAD3-related features (ClinVar, PMIDs: 29392890, 24804794, 34122524). (SP) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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