Submissions for variant NM_005359.6(SMAD4):c.1499T>C (p.Ile500Thr)

dbSNP: rs281875321

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000059734	SCV000617742	pathogenic	not provided	2021-04-20	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22158539, 22585601, 27562837, 22243968, 27302097, 24424121, 24398790, 22683461, 24580733, 24715504, 11977156, 25252769, 30921096, 31654632, 32917212)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000023060	SCV000693905	pathogenic	Myhre syndrome	2017-06-26	criteria provided, single submitter	research	Previously reported pathogenic variant, de novo in this case with maternity and paternity confirmed (PS2).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000023060	SCV001429395	pathogenic	Myhre syndrome	2019-05-09	criteria provided, single submitter	clinical testing
3billion	RCV000023060	SCV002058786	pathogenic	Myhre syndrome	2022-01-03	criteria provided, single submitter	clinical testing	The variant has been previously reported as de novo in a similarly affected individual (PMID: 22243968, PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030149, PMID:2215 8539, PS1_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.776, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030150, PMID:22158539,22158539, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV001852006	SCV002157123	pathogenic	Juvenile polyposis syndrome	2021-03-25	criteria provided, single submitter	clinical testing	Experimental studies have shown that this variant affects SMAD4 protein function (PMID: 31654632, 22158539). This variant has been observed in individual(s) with Myhre syndrome (PMID: 22158539, 27302097, 30921096, 24424121, 22243968). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30149). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 500 of the SMAD4 protein (p.Ile500Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant disrupts the p.Ile500 amino acid residue in SMAD4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22158539, 22243968, 22585601, 24398790, 26636501, 27302097, 24398790). 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV000023060	SCV002570393	pathogenic	Myhre syndrome	2022-07-13	criteria provided, single submitter	clinical testing	This SMAD4 variant (rs281875321) is absent from a large population dataset and has been reported in ClinVar. This missense change has been identified in multiple unrelated individuals with Myhre syndrome. Ile500 lies in the MAD homology 2 (MH2) domain, a region at the C-terminus of the protein, which is required for TGF-beta/BMP signal transduction. Experiments using cultured skin fibroblasts from a patient with the p.Ile500Thr substitution showed decreased levels of SMAD4 ubiquitination with increased levels of SMAD4 protein, enhanced levels of phosphorylated SMAD2/3 and SMAD1/5/8 proteins, and decreased mRNA levels of downstream TGF-beta and BMP target genes compared to controls. This variant was not detected in specimens provided by the patient's mother and father and is apparently de novo. We consider c.1499T>C to be pathogenic.
OMIM	RCV000023060	SCV000044351	pathogenic	Myhre syndrome	2012-06-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000059734	SCV000091304	not provided	not provided		no assertion provided	not provided
Unit U781; INSERM (Institut National de la Santé Et de la Recherche Médicale)	RCV000023060	SCV000106024	pathogenic	Myhre syndrome		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
GeneReviews	RCV000023060	SCV000564087	not provided	Myhre syndrome		no assertion provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000059734	SCV000692040	pathogenic	not provided		no assertion criteria provided	clinical testing