ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.1486C>T (p.Arg496Cys) (rs397518413)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160962 SCV000211671 pathogenic not provided 2018-10-15 criteria provided, single submitter clinical testing This pathogenic variant is denoted SMAD4 c.1486C>T at the cDNA level, p.Arg496Cys (R496C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant was found to occur de-novo in at least three individuals affected with Myhre syndrome (Caputo 2014, Michot 2014). In addition, functional studies by Piccolo et al. (2014) demonstrate that this variant leads to elevated SMAD4 protein levels, increased phosphorylated SMAD2, altered expression of both TGF-beta and BMP target genes, and impaired microfibril deposition causing an extracellular matrix defect. SMAD4 Arg496Cys was not observed in large population cohorts (Lek 2016). This variant is located in the MH2 domain (UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic. This result is indicative of Myhre-LAPS syndrome, a condition characterized by short stature, muscular hypertrophy, facial dysmorphism, joint limitations and intellectual disability. Patients with this syndrome have also been reported to have laryngotracheal stenosis, congenital heart malformations, hearing loss and behavioral disorders (Michot 2014). All SMAD4 pathogenic variants that have been identified to cause Myhre-LAPS syndrome have been observed in the MH2 (MAD homology 2) domain, with a vast majority of pathogenic variants occurring specifically at the Ile500 residue (Le Goff 2012, Caputo 2012, Michot 2014, Piccolo 2014). Additionally, Myhre-LAPS syndrome has been reported to be due to primarily de novo heterozygous missense variants (Le Goff 2012, Michot 2014). In contrast to loss-of-function variants in SMAD4, known to cause Juvenile Polyposis Syndrome (JPS), pathogenic variants associated with Myhre-LAPS syndrome appear to result in a gain-of-function, which is demonstrated by decreased ubiquitination and increased protein levels (Le Goff 2012, Piccolo 2014). Although there has been one report of a patient with Myhre-LAPS syndrome with endometrial cancer and bowel adhesions (Lindor 2012), based on the differing mechanism of these pathogenic variants and long-term follow-up of Myhre-LAPS syndrome patients, there is not a known increased susceptibility to cancer or polyp development associated with this syndrome (Caputo 2012, Michot 2014).
Invitae RCV000541839 SCV000632767 likely pathogenic Juvenile polyposis syndrome 2019-01-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 496 of the SMAD4 protein (p.Arg496Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported to be de novo in three individuals affected with Myhre syndrome (PMID: 24424121, 24715504). ClinVar contains an entry for this variant (Variation ID: 88673). Fibroblasts isolated from an individual carrying this missense change showed increased SMAD4 protein levels, increased levels of phosphorylated SMAD2/total SMAD2 ratio, and up-regulation of matrix metalloproteinases (MMPs), when compared to control cells (PMID: 24398790). The clinical significance of these findings is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional functional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000563137 SCV000672002 pathogenic Hereditary cancer-predisposing syndrome 2016-05-18 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification;Structural Evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification
Ambry Genetics RCV000623811 SCV000742349 pathogenic Inborn genetic diseases 2017-05-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Mendelics RCV000541839 SCV001140894 likely pathogenic Juvenile polyposis syndrome 2019-05-28 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000074360 SCV001365604 pathogenic Myhre syndrome 2020-03-19 criteria provided, single submitter clinical testing The p.Arg496Cys variant in SMAD4 has been reported in at least 12 individuals with Myhre syndrome, and was confirmed as a de novo occurrence in at least four of these individuals (Kenis 2014, Caputo 2014, Michot 2014, Geisheker 2017, Artemis 2019, Meerschaut 2019, Lin 2020, Broad Rare Genomes Project). Additionally, four of these individuals are reported to have neoplasia, including three with endometrial cancer (Lin 2020). This variant has also been reported in ClinVar (Variation ID 88673) and has been identified in 1/10078 of Ashkenazi Jewish and 1/113728 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Structural analysis (Caputo 2014) and in vitro functional studies (Piccolo 2014, Li 2020) provide evidence that the p.Arg496Cys variant may impact protein function. However, these types of assays may not accurately represent biological function. In addition, computational prediction tools and conservation analysis support that the p.Arg496Cys variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for Myhre syndrome in an autosomal dominant manner based upon case counts, de novo occurrence, location at a critical residue, functional evidence, and predicted impact on protein. ACMG/AMP Criteria applied: PS2_VeryStrong, PS4_Moderate, PS3_Supporting, PP3.
Brunetti-Pierri's lab TIGEM RCV000074360 SCV000105966 not provided Myhre syndrome no assertion provided not provided
Unit U781; INSERM (Institut National de la Santé Et de la Recherche Médicale) RCV000074360 SCV000106022 pathogenic Myhre syndrome no assertion criteria provided not provided Converted during submission to Pathogenic.
GeneReviews RCV000074360 SCV000564085 pathogenic Myhre syndrome 2017-01-31 no assertion criteria provided literature only

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