ClinVar Miner

Submissions for variant NM_005359.5(SMAD4):c.667+3G>A (rs757971589)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000358363 SCV000409093 uncertain significance Osler hemorrhagic telangiectasia syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000263575 SCV000409094 uncertain significance Myhre syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000300003 SCV000409095 uncertain significance Juvenile Polyposis 2016-06-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000571451 SCV000675131 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000571451 SCV000691425 likely benign Hereditary cancer-predisposing syndrome 2016-09-05 criteria provided, single submitter clinical testing
GeneDx RCV000607813 SCV000730038 likely benign not specified 2017-06-08 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000635437 SCV000756850 uncertain significance Juvenile polyposis syndrome 2018-05-24 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the SMAD4 gene. It does not directly change the encoded amino acid sequence of the SMAD4 protein, but it affects a nucleotide within the consensus splice site of the intron. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with SMAD4-related disease. ClinVar contains an entry for this variant (Variation ID: 327111). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing, but this prediction has not been confirmed by published transcriptional studies. 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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