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

gnomAD frequency: 0.00002  dbSNP: rs398124368

Total submissions: 6

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	2024-01-10	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	2021-10-22	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 well conserved on limited sequence alignment. In silico splice site analysis for this alteration is inconclusive. 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