ClinVar Genomic variation as it relates to human health

Variant summary: SMAD4 c.1082G>A (p.Arg361His) 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 251392 control chromosomes. c.1082G>A has been reported in the literature in individuals affected with Juvenile Polyposis Syndrome or hereditary hemorrhagic telangiectasia. These data indicate that the variant is associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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, 10764709, 16613914, 17873119, 20101697). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SMAD4 function (PMID: 15014009, 27595937). 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: 24832). This missense change has been observed in individuals with juvenile polyposis syndrome (JPS), hereditary hemorrhagic telangiectasia (HHT) and a combined syndrome including features of both diseases (JPHT) (PMID: 10797267, 17873119, 20101697, 22331366). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 361 of the SMAD4 protein (p.Arg361His).

Published functional studies demonstrate a damaging effect: inhibition of SMAD2 binding and defective down regulation of c-myc in a TGF-beta-dependent manner (Wu 2001, Lim 2006); Not observed in large population cohorts (Lek 2016); 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: 26046389, 10340381, 22331366, 10797267, 11274206, 27595937, 23139211, 24525918, 17873119, 20101697, 17132729, 28693246, 32300199)

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 33326750, 27595937, 17132729, 11274206]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10797267, 17873119, 22331366].

The p.R361H pathogenic mutation (also known as c.1082G>A), located in coding exon 8 of the SMAD4 gene, results from a G to A substitution at nucleotide position 1082. The arginine at codon 361 is replaced by histidine, an amino acid with highly similar properties. This mutation has been reported in multiple individuals with a clinical diagnosis of juvenile polyposis syndrome (JPS) and several also with a diagnosis of hereditary hemorrhagic telangiectasia (HHT) (Kim IJ et al. Int. J. Cancer, 2000 May;86:529-32; Aretz S et al. J. Med. Genet., 2007 Nov;44:702-9). This mutation was shown through in vitro interaction assays to disrupt Smad2/Smad4 heterocomplex formation (Wu JW et al. J. Biol. Chem., 2001 Jun;276:20688-94). In addition, multiple other alterations at the same codon (p.R361C, p.R361G, p.R361L, p.R361S) have also been described in individuals with clinical JPS as well as combined JPS-HHT (Gallione C et al. Am. J. Med. Genet. A, 2010 Feb;152A:333-9; Houlston R et al. Hum. Mol. Genet., 1998 Nov;7:1907-12; Howe JR et al. J. Med. Genet., 2004 Jul;41:484-91). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.