Submissions for variant NM_005359.6(SMAD4):c.1498A>G (p.Ile500Val)

dbSNP: rs281875322

Total submissions: 39

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000059733	SCV000211666	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as p.(I500V) resulted in dysregulation of both matrix metalloproteinases and related inhibitors (Piccolo et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26633542, 34620752, 34556655, 34849273, 22243968, 22585601, 22158539, 27302097, 26636501, 27562837, 25533962, 25363768, 28991257, 28191890, 30921096, 29230941, 28562390, 28867141, 31654632, 32021609, 32175297, 31618753, 31447099, 28714951, 32371413, 32368696, 34015905, 30787465, 31785789, 17873119, 18823382, 15235019, 24398790)
Eurofins Ntd Llc (ga)	RCV000059733	SCV000706695	pathogenic	not provided	2017-03-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004558272	SCV000741420	pathogenic	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2021-07-09	criteria provided, single submitter	clinical testing	The c.1498A>G (p.I500V) alteration is located in exon 12 (coding exon 11) of the SMAD4 gene. This alteration results from an A to G substitution at nucleotide position 1498, causing the isoleucine (I) at amino acid position 500 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD), the SMAD4 c.1498A>G alteration was observed in <0.01% (1/251462) of total alleles studied. This alteration has been previously reported as de novo in multiple unrelated patients with Myhre syndrome and affects a known mutational hotspot (Le Goff, 2011; Caputo, 2012; Lin 2016; Alagia, 2018; Yu, 2019; Varenyiova, 2020). This amino acid position is highly conserved in available vertebrate species. Functional analysis demonstrated that the p.I500V alteration interferes with ubiquitination and degradation of SMAD4 resulting in accumulation of protein and induction of the TGFbeta pathway (Le Goff, 2011; Caputo, 2012; Piccolo, 2014). The in silico prediction for the p.I500V alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000023061	SCV000746947	pathogenic	Myhre syndrome	2017-12-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001376590	SCV000756840	pathogenic	Juvenile polyposis syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 500 of the SMAD4 protein (p.Ile500Val). This variant is present in population databases (rs281875322, gnomAD 0.0009%). This missense change has been observed in individual(s) with Myhre syndrome (PMID: 22158539, 22243968, 22585601, 24398790, 26636501, 27302097). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30150). 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: 24398790). 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, 22683461). 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000023061	SCV000803811	pathogenic	Myhre syndrome	2017-12-19	criteria provided, single submitter	clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000635427	SCV000840072	pathogenic	Generalized juvenile polyposis/juvenile polyposis coli	2018-04-27	criteria provided, single submitter	clinical testing	SMAD4, c.1498A>G, p.Ile500Val The c.1498A>G (p. Ile500Val) variant in the SMAD4 gene has been reported in multiple individuals with MYRHE syndrome (PMID 22158539, 22243968, 22585601, 24398790, 26636501, 27302097). This variant is observed with an ultra-low minor allele frequency in the gnomAD database (1/246232). This variant is on a known mutation hot spot with another pathogenic variant p.Ile500Thr. Functional studies on this variant suggested increased SMAD4 protein levels and increased TGF-beta signaling (PMID 24398790). Therefore, the c.1498A>G (p. Ile500Val) variant in the SMAD4 gene is classified as pathogenic
Fulgent Genetics, Fulgent Genetics	RCV000763031	SCV000893500	pathogenic	Myhre syndrome; Generalized juvenile polyposis/juvenile polyposis coli; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Carcinoma of pancreas	2018-10-31	criteria provided, single submitter	clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV001249691	SCV001423686	pathogenic	Myhre syndrome; Generalized juvenile polyposis/juvenile polyposis coli; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2019-03-11	criteria provided, single submitter	clinical testing	[ACMG/AMP: PS2, PS3, PM1, PM2, PM5, PP2, PP3, PP5] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a novel missense change at an amino residue where a different missense change has been deemed to be pathogenic [PM5], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3], was reported as a pathogenic/likely pathogenic alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory) [PP5].
Institute of Human Genetics, University of Leipzig Medical Center	RCV000023061	SCV001429438	pathogenic	Myhre syndrome	2018-11-08	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000023061	SCV001430132	pathogenic	Myhre syndrome	2019-09-05	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Strasbourg University Hospital	RCV001260808	SCV001437902	pathogenic	Intellectual disability	2020-09-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000023061	SCV001521647	pathogenic	Myhre syndrome	2020-09-21	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genomic Medicine Lab, University of California San Francisco	RCV001375955	SCV001572943	pathogenic	Neurodevelopmental delay	2020-04-16	criteria provided, single submitter	clinical testing
3billion	RCV000023061	SCV002012215	pathogenic	Myhre syndrome	2021-10-02	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030150.18, PS1). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.00000397, PM2). A different missense change at the same codon (p.Ile500Thr) has been reported as pathogenic (ClinVar ID:VCV000030149.3, PM5). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.71, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
DASA	RCV001376590	SCV002061175	pathogenic	Juvenile polyposis syndrome	2022-01-05	criteria provided, single submitter	clinical testing	The c.1498A>G;p.(Ile500Val) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 30150; OMIM: 600993.0016; PMID: 28406602; 22158539; 22243968; 22585601; 24398790; 26636501; 27302097) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID 24398790) - PS3. This variant is not present in population databases (rs281875322, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (ClinVar ID: 30149) - PM5. Missense variant in SMAD4 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Provincial Medical Genetics Program of British Columbia, University of British Columbia	RCV000023061	SCV002320836	pathogenic	Myhre syndrome	2022-01-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000023061	SCV002557760	pathogenic	Myhre syndrome	2022-06-24	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 and are associated with juvenile intestinal polyposis or juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (MIM#174900, MIM#175050), and Myhre syndrome (MIM#139210), respectively (OMIM, 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 isoleucine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated MH2 domain (DECIPHER). (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Ile500Thr) has been classified as pathogenic by several clinical laboratories in ClinVar. (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar and has been observed as de novo in several individuals with syndromic developmental delay or intellectual disability (DECIPHER). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000023061	SCV002577435	pathogenic	Myhre syndrome	2022-08-23	criteria provided, single submitter	clinical testing	PM1, PM2, PM5, PP3, PP5
MGZ Medical Genetics Center	RCV000023061	SCV002580375	pathogenic	Myhre syndrome	2022-04-13	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000059733	SCV003802792	pathogenic	not provided	2022-11-26	criteria provided, single submitter	clinical testing	The SMAD4 c.1498A>G (p.Ile500Val) missense variant results in the substitution of isoleucine at amino acid position 500 with valine. This variant is the most commonly reported variant in Myhre syndrome and has been described in at least 34 affected individuals, in many of whom it occurred de novo (PMID: 27302097; PMID: 36194927). The c.1498A>G variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000009 in the European (non-Finnish) population (version 2.1.1). Two other missense changes affecting the same position, p.Ile500Thr and p.Ile500Met, have also been reported in individuals with Myhre syndrome (PMID: 27302097). The valine and threonine changes have been shown to disrupt TGF-β and BMP signaling in HEK293T cells and patient fibroblasts, and the p.Ile500Val variant has been specifically shown to have a dominant-negative effect on wild-type SMAD4 (PMID: 22158539; PMID 36194927). Based on the available evidence, the c.1498A>G (p.Ile500Val) variant is classified as pathogenic for Myhre syndrome.
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine	RCV000023061	SCV003803884	pathogenic	Myhre syndrome	2021-03-04	criteria provided, single submitter	clinical testing
Duke University Health System Sequencing Clinic, Duke University Health System	RCV000023061	SCV003919034	pathogenic	Myhre syndrome	2023-04-20	criteria provided, single submitter	research
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000059733	SCV004026072	pathogenic	not provided	2022-06-27	criteria provided, single submitter	clinical testing	PM1, PS3, PP3, PM5, PM2_SUP
CeGaT Center for Human Genetics Tuebingen	RCV000059733	SCV005042338	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	SMAD4: PS2:Very Strong, PM1, PM2, PM5, PP2, PP3, PS3:Supporting, PS4:Supporting
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000059733	SCV005198290	pathogenic	not provided	2024-03-26	criteria provided, single submitter	clinical testing
OMIM	RCV000023061	SCV000044352	pathogenic	Myhre syndrome	2012-06-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000059733	SCV000091303	not provided	not provided		no assertion provided	not provided
Unit U781; INSERM (Institut National de la Santé Et de la Recherche Médicale)	RCV000023061	SCV000106023	pathogenic	Myhre syndrome		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
GeneReviews	RCV000023061	SCV000564086	not provided	Myhre syndrome		no assertion provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000059733	SCV000692039	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000059733	SCV000778276	pathogenic	not provided	2017-07-31	no assertion criteria provided	clinical testing
Shieh Lab, University of California, San Francisco	RCV000023061	SCV001441640	pathogenic	Myhre syndrome	2020-10-19	no assertion criteria provided	research
Pediatric Genetics Clinic, Sheba Medical Center	RCV000023061	SCV001712225	pathogenic	Myhre syndrome	2021-05-13	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000059733	SCV001808895	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000059733	SCV001926924	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000059733	SCV001953780	pathogenic	not provided		no assertion criteria provided	clinical testing
Institute of Human Genetics, Heidelberg University	RCV000023061	SCV001983777	pathogenic	Myhre syndrome	2021-10-20	no assertion criteria provided	clinical testing
Molecular Diagnosis Center for Deafness	RCV000023061	SCV002072466	pathogenic	Myhre syndrome	2021-11-02	no assertion criteria provided	clinical testing