ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.1651T>G (p.Leu551Val) (rs1064793950)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485032 SCV000567435 uncertain significance not provided 2015-07-27 criteria provided, single submitter clinical testing This variant is denoted SMAD4 c.1651T>G at the cDNA level, p.Leu551Val (L551V) at the protein level, and results in the change of a Leucine to a Valine (TTA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. SMAD4 Leu551Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. SMAD4 Leu551Val occurs at a position that is conserved across species and is located in the MH2 domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether SMAD4 Leu551Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000694076 SCV000822503 uncertain significance Juvenile polyposis syndrome 2018-03-21 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 551 of the SMAD4 protein (p.Leu551Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SMAD4-related disease. ClinVar contains an entry for this variant (Variation ID: 419554). 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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