ClinVar Miner

Submissions for variant NM_020975.6(RET):c.867+4del

gnomAD frequency: 0.00002  dbSNP: rs398124368
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000082058 SCV000113997 uncertain significance not provided 2013-07-25 criteria provided, single submitter clinical testing
Invitae RCV000550028 SCV000658501 uncertain significance Multiple endocrine neoplasia, type 2 2021-11-24 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the RET gene. It does not directly change the encoded amino acid sequence of the RET protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs398124368, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 95998). Variants that disrupt 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 may disrupt the consensus splice site. 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.
Ambry Genetics RCV000563030 SCV000674832 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-18 criteria provided, single submitter clinical testing The c.867+4delC intronic variant, located in intron 4 of the RET gene, results from a deletion of one nucleotide within intron 4 of the RET gene. This nucleotide position is poorly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000082058 SCV002072825 uncertain significance not provided 2021-08-02 criteria provided, single submitter clinical testing In silico analysis supports a deleterious effect on splicing; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Sema4,Sema4 RCV000563030 SCV002527929 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-10 criteria provided, single submitter curation
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678745 SCV000804917 likely benign Aganglionic megacolon 2008-08-28 no assertion criteria provided clinical testing

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