ClinVar Miner

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

dbSNP: rs281875322
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Total submissions: 37
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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 RCV000624818 SCV000741420 pathogenic Inborn genetic diseases 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
Invitae 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
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

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