Submissions for variant NM_005359.6(SMAD4):c.1081C>G (p.Arg361Gly)

dbSNP: rs80338963

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002228051	SCV000756844	pathogenic	Juvenile polyposis syndrome	2022-01-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg361 amino acid residue in SMAD4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9811934, 17873119, 20101697, 27595937). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 24830). This missense change has been observed in individual(s) with juvenile polyposis and/or SMAD4-related conditions (PMID: 15031030, 18823382). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 361 of the SMAD4 protein (p.Arg361Gly).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470716	SCV002768027	pathogenic	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function is associated with juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (MIM#175050), while specific gain of function variants are associated with Myhre syndrome (MIM#139210) (PMID:31837202). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated MH2 domain (Pfam). (I) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Alternative missense changes at this codon to cysteine, histidine, and leucine have been described multiple times each in individuals with juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP-HTT) (ClinVar, PMID:16613914, 22331366). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with JP-HTT or juvenile polyposis without hereditary hemorrhagic telangiectasia (ClinVar, PMID:15031030, 15235019, 18823382). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Database of Curated Mutations (DoCM)	RCV000425278	SCV000507402	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436432	SCV000507403	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418748	SCV000507404	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428136	SCV000507405	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438396	SCV000507406	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418132	SCV000507407	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428393	SCV000507408	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441273	SCV000507409	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only