ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.1245_1248delCAGA (p.Asp415Glufs) (rs80338965)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131266 SCV000186232 pathogenic Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Deficient protein function in appropriate functional assay(s)
GeneDx RCV000254690 SCV000211665 pathogenic not provided 2018-10-11 criteria provided, single submitter clinical testing This deletion of 4 nucleotides is denoted SMAD4 c.1245_1248delCAGA at the cDNA level and p.Asp415GlufsX20 (D415EfsX20) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TAGA[delCAGA]GAAG. The deletion causes a frameshift, which changes an Aspartic Acid to a Glutamic Acid at codon 415, and creates a premature stop codon at position 20 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. SMAD4 c.1245_1248delCAGA, also published as 1244_1247delACAG and 1372_1375del4 using alternate nomenclature, has been observed in multiple individuals with Juvenile Polyposis Syndrome and hereditary hemorrhagic telangiectasia (Howe 1998, Aretz 2007, Calva-Cerqueira 2009, Gallione 2010, Piepoli 2012, Ngeow 2013, Teekakirikul 2013, Blatter 2015, Burmester 2016) and was shown to decrease BMP-mediated transcriptional activity in a functional study (Carr 2012). We consider this variant to be pathogenic.
Invitae RCV000205495 SCV000259936 pathogenic Juvenile polyposis syndrome 2018-12-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp415Glufs*20) in the SMAD4 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families affected with juvenile polyposis syndrome (JPS) (PMID: 9582123, 17873119, 23399955, 18355998, 23239472, 27375208), with evidence of segregation with disease (PMID: 9582123). It is also described as 1244_7delACAG and as a 4-bp deletion between nucleotides 1372 and 1375 in the literature. ClinVar contains an entry for this variant (Variation ID: 142253). An experimental study has shown that this variant affects SMAD4 protein function, leading to reduced bone morphogenetic protein (BMP) signaling (PMID: 22316667). Loss-of-function variants in SMAD4 are known to be pathogenic (PMID: 16152648, 16436638, 22810475). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254690 SCV000889841 pathogenic not provided 2018-06-04 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768095 SCV000898987 pathogenic Myhre syndrome; Juvenile polyposis syndrome; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Carcinoma of pancreas 2018-09-07 criteria provided, single submitter clinical testing SMAD4 NM_005359.5 exon 10 p.Asp415Glufs*20 (c.1245_1248delCAGA): This variant has been reported in the literature (alternate nomenclature: c.1244_1247del, c.1242_1245delAGAC, c.1372_1375del4) in multiple individuals with juvenile polyposis syndrome (JPS) (Howe 1998 PMID:9582123, Aretz 2007 PMID:17873119, Pintiliciuc 2008 PMID:18355998, Calva-Cerqueira 2009 PMID:18823382, Piepoli 2012 PMID:22748914, Ngeow 2013 PMID:23399955, Blatter 2015 PMID:26171675, Burmester 2016 PMID:27375208) and was shown to segregate with disease in several affected family members (Howe 1998 PMID:9582123, Piepoli 2012 PMID:22748914, Burmester 2016 PMID:27375208). This variant was also identified in an individual presenting with JPS, hereditary hemorrhagic telangiectasia (HTT), and features of syndromic TAAD (Teekakirikul 2013 PMID:23239472). This variant is not present in large control databases, and it is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:142253). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. However, an in vitro functional study showed significantly decreased luciferase activity with this deletion, which is suggested to have a negative impact on downstream BMP signaling (Carr 2012 PMID:22316667). However, these studies may not accurately represent in vivo biological function. This variant is a deletion of 4 nucleotides and creates a premature stop codon 20 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants have been described as a mechanism of disease for this gene (Gallione 2010 PMID:20101697). In summary, this variant is classified as pathogenic based on the data above.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000205495 SCV000966985 pathogenic Juvenile polyposis syndrome 2018-07-03 criteria provided, single submitter clinical testing The p.Asp415GlufsX20 variant in SMAD4 has been reported in >20 probands (2 de no vo occurrences) with juvenile polyposis syndrome (JPS) and segregated with disea se in >20 relatives of multiple families (Howe 1998, Handra-Luca 2005, Calva-Cer queira 2009, Piepoli 2012, Ngeow 2013, Teekakirikul 2013, AlBalwi 2015, Susswein 2015, Burmester 2016, DeRycke 2017). This variant was absent from large populat ion databases but has been reported in ClinVar (Variation ID: 142253). This vari ant is predicted to cause a frameshift, which alters the protein?s amino acid se quence beginning at position 415 and leads to a premature termination codon 20 a mino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the SMAD4 gene is an establi shed disease mechanism in JPS. In addition, in vitro functional studies provide some evidence that the p.Asp415GlufsX20 variant may impact protein function (Car r 2012). In summary, this variant meets criteria to be classified as pathogenic for JPS in an autosomal dominant manner based upon prevalence in probands, segre gation studies, absence from controls, functional evidence, and the predicted im pact on protein. ACMG/AMP Criteria applied: PVS1, PS4, PM6_Strong, PP1_Strong, P M2.
GeneReviews RCV000205495 SCV000041150 pathologic Juvenile polyposis syndrome 2011-09-29 no assertion criteria provided curation Converted during submission to Pathogenic.
Research and Development, ARUP Laboratories RCV000021727 SCV000042393 pathogenic Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.
Research and Development, ARUP Laboratories RCV000205495 SCV000042395 pathogenic Juvenile polyposis syndrome 2012-12-04 no assertion criteria provided clinical testing Converted during submission to Pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000254690 SCV000692037 pathogenic not provided no assertion criteria provided clinical testing

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