ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.521C>A (p.Thr174Asn) (rs138800446)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617133 SCV000671971 uncertain significance Cardiovascular phenotype 2017-10-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000567416 SCV000686542 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-23 criteria provided, single submitter clinical testing
Counsyl RCV000168261 SCV000786392 uncertain significance Juvenile polyposis syndrome 2018-04-24 criteria provided, single submitter clinical testing
GeneDx RCV000236619 SCV000293595 uncertain significance not provided 2018-11-20 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.521C>A at the cDNA level, p.Thr174Asn (T174N) at the protein level, and results in the change of a Threonine to an Asparagine (ACT>AAT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. SMAD4 Thr174Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Linker domain (Howe 2004, Calva-Cerqueira 2009, Massague 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether SMAD4 Thr174Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000168261 SCV000218932 uncertain significance Juvenile polyposis syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with asparagine at codon 174 of the SMAD4 protein (p.Thr174Asn). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and asparagine. This variant is present in population databases (rs138800446, ExAC 0.05%). This variant has not been reported in the literature in individuals with SMAD4-related disease. ClinVar contains an entry for this variant (Variation ID: 188279). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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