Submissions for variant NM_005359.6(SMAD4):c.1054G>A (p.Gly352Arg)

dbSNP: rs121912581

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000059731	SCV001245854	pathogenic	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731312	SCV001983596	pathogenic	Juvenile polyposis syndrome	2021-09-02	criteria provided, single submitter	clinical testing	Variant summary: SMAD4 c.1054G>A (p.Gly352Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251432 control chromosomes. c.1054G>A has been reported in the literature in multiple individuals affected with Juvenile Polyposis Syndrome (Sayad_2002, Gallione_2004, Howe_2004, Calva-Cerqueira_2009). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001731312	SCV003443790	likely pathogenic	Juvenile polyposis syndrome	2021-12-29	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 352 of the SMAD4 protein (p.Gly352Arg). This missense change has been observed in individual(s) with clinical features of juvenile polyposis syndrome and hereditary hemorrhagic telangiectasia (PMID: 12417513, 15031030, 15235019, 18823382). It has also been observed to segregate with disease in related individuals. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly352 amino acid residue in SMAD4. Other variant(s) that disrupt this residue have been observed in individuals with SMAD4-related conditions (PMID: 20101697), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects SMAD4 function (PMID: 31515488). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMAD4 protein function. ClinVar contains an entry for this variant (Variation ID: 24827).
OMIM	RCV000009075	SCV000029292	pathogenic	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2004-03-13	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000059731	SCV000091301	not provided	not provided		no assertion provided	not provided