ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.38A>G (p.Asn13Ser) (rs281875323)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000059736 SCV000567059 uncertain significance not provided 2016-09-27 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.38A>G at the cDNA level, p.Asn13Ser (N13S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has been reported in an individual with idiopathic pulmonary arterial hypertension and in 1/62 healthy East Asian individuals undergoing whole genome sequencing (Nasim 2011, Bodian 2014). Of note, the participants in Bodian et al. (2014) study were younger than 50 years old thus the unaffected status of this individual may not be significant. In functional assays, SMAD4 Asn13Ser did not impact SMAD-mediated signaling or interaction with Lmo4, Rassf5 and Smad9 (Nasim 2011, Wei 2014). SMAD4 Asn13Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. SMAD4 Asn13Ser occurs at a position that is conserved across species and is not located in a known functional domain (Uniprot). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether SMAD4 Asn13Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000561032 SCV000672010 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000662613 SCV000785271 uncertain significance Juvenile polyposis syndrome 2017-06-23 criteria provided, single submitter clinical testing
Color RCV000561032 SCV000906007 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000122056 SCV000920228 uncertain significance not specified 2018-09-07 criteria provided, single submitter clinical testing Variant summary: SMAD4 c.38A>G (p.Asn13Ser) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249274 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.38A>G in individuals affected with Juvenile Polyposis Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. This variant has been described in a patient with idiopathic pulmonary arterial hypertension (Nasim 2011). At least two publications reported experimental evidence evaluating an impact on protein function. These results showed no damaging effect for the variant on protein stability, subcellular localization, signaling activity and interactions with Smad3, Lmo4, Rassf5, and Smad9 (Nasim 2011, Wei 2014). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ITMI RCV000122056 SCV000086267 not provided not specified 2013-09-19 no assertion provided reference population
UniProtKB/Swiss-Prot RCV000059736 SCV000091306 not provided not provided no assertion provided not provided
Medical & Molecular Genetics Group,University of Lincoln RCV000488661 SCV000576362 uncertain significance Primary pulmonary hypertension no assertion criteria provided literature only

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