18-51078294-C-T
Variant summary
Our verdict is Pathogenic. The variant received 10 ACMG points: 14P and 4B. PM1PP3_StrongPP5_Very_StrongBS2
The NM_005359.6(SMAD4):c.1486C>T(p.Arg496Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R496H) has been classified as Uncertain significance.
Frequency
Consequence
NM_005359.6 missense
Scores
Clinical Significance
Conservation
Publications
- juvenile polyposis/hereditary hemorrhagic telangiectasia syndromeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, PanelApp Australia
- Myhre syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
- generalized juvenile polyposis/juvenile polyposis coliInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
- juvenile polyposis syndromeInheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- familial thoracic aortic aneurysm and aortic dissectionInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- hereditary hemorrhagic telangiectasiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- pulmonary arterial hypertensionInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 10 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SMAD4 | NM_005359.6 | c.1486C>T | p.Arg496Cys | missense_variant | Exon 12 of 12 | ENST00000342988.8 | NP_005350.1 | |
| SMAD4 | NM_001407041.1 | c.1486C>T | p.Arg496Cys | missense_variant | Exon 12 of 12 | NP_001393970.1 | ||
| SMAD4 | NM_001407042.1 | c.1486C>T | p.Arg496Cys | missense_variant | Exon 12 of 12 | NP_001393971.1 | ||
| SMAD4 | NR_176265.1 | n.2137C>T | non_coding_transcript_exon_variant | Exon 13 of 13 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SMAD4 | ENST00000342988.8 | c.1486C>T | p.Arg496Cys | missense_variant | Exon 12 of 12 | 5 | NM_005359.6 | ENSP00000341551.3 |
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00000795 AC: 2AN: 251432 AF XY: 0.0000147 show subpopulations
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727238 show subpopulations
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
Myhre syndrome Pathogenic:9Other:2
ACMG classification criteria: PS2 very strong, PS3 supporting, PS4 moderate, PP3
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.
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
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
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.
not provided Pathogenic:10
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.
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)
SMAD4: PS2, PS4, PP2, PP3
SMAD4-related disorder Pathogenic:1
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.
Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
The c.1486C>T (p.R496C) alteration is located in exon 12 (coding exon 11) of the SMAD4 gene. This alteration results from a C to T substitution at nucleotide position 1486, causing the arginine (R) at amino acid position 496 to be replaced by a cysteine (C). for Myhre syndrome; however, its clinical significance for juvenile polyposis syndrome/hereditary hemorrhagic telangiectasia syndrome is uncertain. Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/251432) total alleles studied. The highest observed frequency was 0.01% (1/10078) of Ashkenazi Jewish alleles. This alteration has been reported in several individuals with a de novo clinical diagnosis of Myhre syndrome (Le Goff, 2014; Kenis, 2014; Michot, 2014). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). 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, 2014). 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, 2014). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Carcinoma of pancreas;C0345893:Juvenile polyposis syndrome;C0796081:Myhre syndrome;C1832942:Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Pathogenic:1
Generalized juvenile polyposis/juvenile polyposis coli Pathogenic:1
Intellectual disability Pathogenic:1
Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome Pathogenic:1
Variant confirmed as disease-causing by referring clinical team
Moyamoya angiopathy Pathogenic:1
Juvenile polyposis syndrome Pathogenic:1
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.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at