ClinVar Miner

Submissions for variant NM_005359.6(SMAD4):c.38A>G (p.Asn13Ser)

gnomAD frequency: 0.00001  dbSNP: rs281875323
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000059736 SCV000567059 uncertain significance not provided 2023-07-21 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest no damaging effect: did not impact SMAD-mediated signaling or interaction with Lmo4, Rassf5 and Smad9 (Nasim et al., 2011; Wei et al., 2014); Reported in an individual with idiopathic pulmonary arterial hypertension and in 1/62 healthy East Asian individuals undergoing whole genome sequencing (Nasim et al., 2011; Bodian et al., 2014); This variant is associated with the following publications: (PMID: 25502805, 26387786, 21898662, 30084161, 24728327, 31515488)
Ambry Genetics RCV002311543 SCV000672010 likely benign Familial thoracic aortic aneurysm and aortic dissection; Hereditary cancer-predisposing syndrome 2022-08-02 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl RCV000662613 SCV000785271 uncertain significance Generalized juvenile polyposis/juvenile polyposis coli 2017-06-23 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000561032 SCV000906007 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Invitae RCV001293427 SCV001393601 uncertain significance Juvenile polyposis syndrome 2023-11-28 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 13 of the SMAD4 protein (p.Asn13Ser). This variant is present in population databases (rs281875323, gnomAD 0.0009%). This missense change has been observed in individual(s) with pulmonary arterial hypertension (PMID: 21898662). ClinVar contains an entry for this variant (Variation ID: 68788). 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 does not substantially affect SMAD4 function (PMID: 21898662, 25502805, 31515488). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc. RCV003315582 SCV004017811 uncertain significance Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 2023-04-10 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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
Rare Disease Genomics Group, St George's University of London RCV000488661 SCV000576362 uncertain significance Pulmonary hypertension, primary, 1 no assertion criteria provided literature only

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