ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1893_1898del (p.Asp631_Leu633delinsGlu)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Division of Medical Genetics,Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi RCV001267832 SCV001443814 likely pathogenic Multiple endocrine neoplasia, type 2b 2020-11-19 criteria provided, single submitter clinical testing The p.Asp631_Leu633delinsGlu variant, not reported in population databases, was identified in a female child with a clinical picture resembling the MEN2B phenotype. Segregation analysis undertaken in the family demonstrated that it occurred "de novo". This variant is very similar to a somatic in-frame deletion studied by Borganzone et al (1999), p.Glu632_Leu633del (c.1894_1899delGAGCTG), that reduces the spacing between two Cysteine residues, causing ligand-independent constitutive dimerization and activation of RET. Although in the p.Asp631_Leu633delinsGlu variant the deletion is shifted by 1 bp compared to the alteration described by Borganzone et al, it results in the deletion of two amino acids in the same location: thus, the final effect, that is the constitutive activation of RET signaling, is likely to be the same. Collectively taken, the "de novo" origin in the patient, her clinical phenotype, and the functional data support the hypothesis that the p.Asp631_Leu633delinsGlu variant is causative of MEN2B and should be assigned to the HST/H risk class.

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