Submissions for variant NM_005359.6(SMAD4):c.1081C>T (p.Arg361Cys)

dbSNP: rs80338963

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376609	SCV000218955	pathogenic	Juvenile polyposis syndrome	2023-10-30	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 361 of the SMAD4 protein (p.Arg361Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with juvenile polyposis syndrome (JPS) and/or hereditary hemorrhagic telangiectasia (HHT) (PMID: 9811934, 10764709, 16613914, 17873119, 20101697). ClinVar contains an entry for this variant (Variation ID: 8543). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMAD4 protein function. Experimental studies have shown that this missense change affects SMAD4 function (PMID: 9214508, 11583957). 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: 10797267, 15031030, 15235019, 20101697, 22316667). 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.
Ambry Genetics	RCV002311508	SCV000671966	pathogenic	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	clinical testing	The p.R361C pathogenic mutation (also known as c.1081C>T), located in coding exon 8 of the SMAD4 gene, results from a C to T substitution at nucleotide position 1081. The arginine at codon 361 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple patients with a clinical diagnosis of juvenile polyposis syndrome (JPS) (Houlston R et al. Hum. Mol. Genet. 1998; 7:1907-12, Aretz S et al. J. Med. Genet. 2007; 44:702-9), as well as in multiple patients with combined juvenile polyposis - hereditary hemorrhagic telangiectasia (JP-HHT) syndrome (Gallione C et al. Am. J. Med. Genet. A 2010; 152A:333-9; Jelsig AM et al. Clin Genet. 2016 Jul;90(1):55-62). This alteration has also been reported in a hereditary hemorrhagic telangiectasia (HHT) cohort (Shovlin CL et al. Blood, 2020 10;136:1907-1918). This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Multiple other alterations at this same codon (p.R361G, p.R361H, p.R361L, p.R361S) have also been described in individuals with clinical JPS. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000009072	SCV001439412	pathogenic	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2018-01-01	criteria provided, single submitter	research	PM2+PM1+PP2+PP4
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000059732	SCV001471548	pathogenic	not provided	2019-11-06	criteria provided, single submitter	clinical testing	The SMAD4 c.1081C>T; p.Arg361Cys variant (rs80338963) is reported in the literature in multiple individuals affected with hereditary hemorrhagic telangiectasia (HHT) or juvenile polyposis syndrome (JPS) (Aretz 2007, Gallione 2006, Gallione 2010, Houlston 1998, Woodford-Richens 2001). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at amino acid 361 is highly conserved, and functional analyses suggest that this variant exhibits deficient homo-oligomerization and deficient binding to other partner proteins (Shi 1997), which may result in instability and degradation (Woodford-Richens 2001). Additionally, other amino acid substitutions at this codon (Gly, His, Leu, Ser) have been reported in individuals with HHT or JPS and are considered disease-causing (Aretz 2007, Gallione 2010, Howe 2004). Based on available information, the p.Arg361Cys variant is considered to be pathogenic. References: Aretz S et al. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet. 2007 Nov;44(11):702-9. Gallione C et al. Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome. Am J Med Genet A. 2010 Feb;152A(2):333-9. Gallione CJ et al. SMAD4 mutations found in unselected HHT patients. J Med Genet. 2006 Oct;43(10):793-7. Houlston et al. Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases. Hum Mol Genet. 1998 Nov;7(12):1907-12. Howe JR et al. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet. 2004 Jul;41(7):484-91. Shi Y et al. A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature. 1997 Jul 3;388(6637):87-93. Woodford-Richens KL et al. Comprehensive analysis of SMAD4 mutations and protein expression in juvenile polyposis: evidence for a distinct genetic pathway and polyp morphology in SMAD4 mutation carriers. Am J Pathol. 2001 Oct;159(4):1293-300.
Mayo Clinic Laboratories, Mayo Clinic	RCV000059732	SCV002103267	pathogenic	not provided	2021-06-02	criteria provided, single submitter	clinical testing	PS4, PM6_strong, PM1, PM5, PM2, PP3
Myriad Genetics, Inc.	RCV000009072	SCV004932964	likely pathogenic	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2024-02-09	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15799969]. This variant is expected to disrupt protein structure [PMID: 9214508]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10764709, 16613914, 20101697, 17873119, 9811934, 15031030].
OMIM	RCV001376609	SCV000029288	pathogenic	Juvenile polyposis syndrome	2006-10-01	no assertion criteria provided	literature only
OMIM	RCV000009072	SCV000029289	pathogenic	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2006-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000009071	SCV000041148	not provided	Generalized juvenile polyposis/juvenile polyposis coli		no assertion provided	literature only
UniProtKB/Swiss-Prot	RCV000059732	SCV000091302	not provided	not provided		no assertion provided	not provided
Database of Curated Mutations (DoCM)	RCV000424666	SCV000504610	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434956	SCV000504611	pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419013	SCV000504612	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429075	SCV000504613	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435832	SCV000504614	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419899	SCV000504615	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430148	SCV000504616	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440366	SCV000504617	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
PreventionGenetics, part of Exact Sciences	RCV003924819	SCV004737753	pathogenic	SMAD4-related disorder	2024-01-25	no assertion criteria provided	clinical testing	The SMAD4 c.1081C>T variant is predicted to result in the amino acid substitution p.Arg361Cys. This variant has been reported in multiple individuals with juvenile polyposis coli and hereditary hemorrhagic telangiectasia syndrome (see for example, Table 1, Woodford-Richens et al. 2000. PubMed ID: 10764709; Table 1, Gallione et al. 2010. PubMed ID: 20101697; Hashimoto et al. 2020. PubMed ID: 32944796). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by other institutions in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/8543/). Alternate nucleotide substitutions affecting the same amino acid (p.Arg361His, p.Arg361Gly, p.Arg361Leu, and p.Arg361Ser), have been reported in multiple individuals with juvenile polyposis coli and hereditary hemorrhagic telangiectasia syndrome (Table 1, Howe et al. 2004. PubMed ID: 15235019; Table 1, Gallione et al. 2004. PubMed ID: 15031030; Table 1, Gallione et al. 2010. PubMed ID: 20101697). The c.1081C>T (p.Arg361Cys) variant is interpreted as pathogenic.