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

gnomAD frequency: 0.00001  dbSNP: rs397518413

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160962	SCV000211671	pathogenic	not provided	2021-11-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect showing elevated SMAD4 levels and impaired microfibril deposition causing an extracellular matrix defect (Piccolo et al., 2014); In silico analysis supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24424121, 24398790, 24715504, 27302097, 28051901, 24841914, 24580733, 28867141, 31654632, 31595668, 31837202, 31447099, 33428109, 30787465, 31785789, 17873119, 18823382, 15235019)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228175	SCV000632767	pathogenic	Juvenile polyposis syndrome	2024-07-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 496 of the SMAD4 protein (p.Arg496Cys). This variant is present in population databases (rs397518413, gnomAD 0.01%). This missense change has been observed in individual(s) with Myhre syndrome (PMID: 24424121, 24715504). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 88673). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on SMAD4 function (PMID: 24398790). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002311544	SCV000672002	pathogenic	Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	The p.R496C pathogenic mutation (also known as c.1486C>T), located in coding exon 11 of the SMAD4 gene, results from a C to T substitution at nucleotide position 1486. The arginine at codon 496 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in several individuals with a de novo clinical diagnosis of Myhre syndrome (Le Goff C et al. Clin. Genet. 2014 Jun; 85(6):503-13; Kenis C et al. Otol. Neurotol. 2014 Oct; 35(9):e253-5; Michot C et al. Eur. J. Hum. Genet. 2014 Nov; 22(11):1272-7). The p.R496C alteration is located in the MH2 domain, which is required for SMAD oligomerization and TGF-β / bone morphogenic protein (BMP) signal transduction. In silico structural analyses suggest that conformational changes promoted by the replacement of arginine at position 496 impacts the stability of the SMAD heterotrimer and proper SMAD4 ubiquitination (Caputo V et al. Am. J. Med. Genet. 2014 Jul; 164A(7):1835-40). Functional consequences of this alteration have been investigated; skin fibroblasts exhibited increased SMAD4 proteins compared with wildtype controls which only showed detectable SMAD4 protein following TGF-β stimulation, increased phosphorylated SMAD2 proteins, matrix metalloproteinase (MMP) overexpression, and impaired microfibril deposition within the extracellular domain (Piccolo P et al. Eur. J. Hum. Genet. 2014 Aug; 22(8):988-94). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is classified as a pathogenic mutation associated with Myhre syndrome.
Mendelics	RCV000541839	SCV001140894	likely pathogenic	Generalized juvenile polyposis/juvenile polyposis coli	2019-05-28	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000160962	SCV001447962	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000160962	SCV001450339	pathogenic	not provided	2016-11-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000074360	SCV001521646	pathogenic	Myhre syndrome	2020-01-22	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
3billion, Medical Genetics	RCV000074360	SCV002058724	pathogenic	Myhre syndrome	2022-01-03	criteria provided, single submitter	clinical testing	The same variant was also reported as de novo in one or more affected individuals with a consistent phenotype from multiple, unrelated families (PMID: 24424121, 31654632, PS2_VS). The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 24424121, 31654632, 31595668, 30968316, PS4_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.961, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). The variantwas confirmed as de novo by parental testing. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000074360	SCV002512467	pathogenic	Myhre syndrome	2021-03-08	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS2 very strong, PS3 supporting, PS4 moderate, PP3
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000074360	SCV002764895	pathogenic	Myhre syndrome	2021-10-27	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000074360	SCV002767131	pathogenic	Myhre syndrome	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 5 - Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. Missense variants result in gain of function effects associated with Myhre syndrome (PMID 22158539; PMID 31837202; PMID 31595668). (N) 0102 - Loss-of-function is a known mechanism of disease for this gene. Premature termination codon variants result in loss of function associated with hereditary haemorrhagic telangiectasia syndrome or juvenile polyposis (OMIM; ClinVar; PMID 31837202). (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a cysteine (exon 12). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and is very highly conserved with a major amino acid change. (P) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (MH2 domain; PDB). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported pathogenic in multiple individuals with Myhre syndrome (ClinVar; Decipher; PMID 31837202; PMID 31595668). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Fulgent Genetics, Fulgent Genetics	RCV002483120	SCV002776909	likely pathogenic	Myhre syndrome; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Carcinoma of pancreas; Juvenile polyposis syndrome	2021-08-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000160962	SCV003819187	pathogenic	not provided	2022-03-30	criteria provided, single submitter	clinical testing
Eurofins-Biomnis	RCV000074360	SCV003935080	pathogenic	Myhre syndrome	2022-11-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000160962	SCV004143108	pathogenic	not provided	2023-10-01	criteria provided, single submitter	clinical testing	SMAD4: PS2, PS4, PP2, PP3
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000160962	SCV005198289	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000160962	SCV005878823	pathogenic	not provided	2024-01-09	criteria provided, single submitter	clinical testing	The SMAD4 c.1486C>T; p.Arg496Cys variant (rs397518413, ClinVar Variation ID: 88673) is found in the literature in several individuals with Myhre Syndrome, with both de novo and inheritance from an affected parent being reported (Caputo 2014, Demir 2023, Lin 2020, Meerschaut 2019, Piccolo 2014, Yang 2022). This variant is only observed on two alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.961). Functional analysis of the variant protein showed increased protein levels and impaired function (Li 2020, Piccolo 2014). Based on available information, this variant is considered to be pathogenic. References: Caputo V et al. Novel SMAD4 mutation causing Myhre syndrome. Am J Med Genet A. 2014 Jul;164A(7):1835-40. PMID: 24715504. Demir S et al. A Second Family with Myhre Syndrome Caused by the Same Recurrent SMAD4 Pathogenic Variation (p.Arg496Cys). Mol Syndromol. 2023 Apr;14(2):175-180. PMID: 37064342. Li H et al. The first two Chinese Myhre syndrome patients with the recurrent SMAD4 pathogenic variants: Functional consequences and clinical diversity. Clin Chim Acta. 2020 Jan;500:128-134. PMID: 31654632. Lin AE et al. Gain-of-function pathogenic variants in SMAD4 are associated with neoplasia in Myhre syndrome. Am J Med Genet A. 2020 Feb;182(2):328-337. PMID: 31837202. Meerschaut I et al. Myhre syndrome: A first familial recurrence and broadening of the phenotypic spectrum. Am J Med Genet A. 2019 Dec;179(12):2494-2499. PMID: 31595668. Piccolo P et al. SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan. Eur J Hum Genet. 2014 Aug;22(8):988-94. PMID: 24398790. Yang DD et al. Natural history of Myhre syndrome. Orphanet J Rare Dis. 2022 Jul 30;17(1):304. PMID: 35907855.
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	not provided	Myhre syndrome		no assertion provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV004703205	SCV001439126	likely pathogenic	Moyamoya angiopathy		no assertion criteria provided	research
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000160962	SCV001799767	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000160962	SCV001808484	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000160962	SCV001956967	pathogenic	not provided		no assertion criteria provided	clinical testing
Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University	RCV000074360	SCV003844088	pathogenic	Myhre syndrome	2021-09-18	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003398656	SCV004110014	pathogenic	SMAD4-related disorder	2023-10-19	no assertion criteria provided	clinical testing	The SMAD4 c.1486C>T variant is predicted to result in the amino acid substitution p.Arg496Cys. This variant has been reported in multiple patients with Myhre syndrome and is a recurrent de novo finding (Caputo et al. 2014. PubMed ID: 24715504; Piccolo et al. 2014. PubMed ID: 24398790). Functional in vitro studies showed an increase in SMAD4 protein in fibroblasts with the p.Arg496Cys variant and altered expression of downstream transcriptional target genes (Piccolo et al. 2014. PubMed ID: 24398790). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-48604664-C-T). It is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/88673/). This variant is interpreted as pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV003584539	SCV004362369	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-07	flagged submission	clinical testing	This missense variant replaces arginine with cysteine at codon 496 of the SMAD4 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have provided evidence that this variant may impact protein function. In vitro studies have shown an increase in SMAD4 protein levels and the phosphorylated SMAD2/total SMAD2 protein ratio (PMID: 24398790), a significant increase in gene expression compared to wild type in transcriptional activation assays (PMID: 31654632), and decreased proliferation, and elevated expression of cellular senescence and inflammatory markers in a cell based assay (PMID: 33428109). In silico structural analyses have also suggested an impact to the stability of the SMAD heterotrimer and/or proper SMAD4 ubiquitination (PMID: 24715504). This variant has been reported in numerous individuals affected with Myhre syndrome (PMID: 22158539, 24398790, 24424121, 24715504, 24841914, 26633542, 28628100, 30968316, 31595668, 31837202). Three individuals were also affected with endometrial cancer (PMID: 31837202). This variant has been identified in 2/251432 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although this variant is considered Pathogenic for autosomal dominant Myhre Syndrome, the available evidence is insufficient to determine the role of this variant in cancer predisposition conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Solve-RD Consortium	RCV004767058	SCV005091325	likely pathogenic	Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team