ClinVar Miner

Submissions for variant NM_020975.6(RET):c.3199C>T (p.Pro1067Ser)

gnomAD frequency: 0.00004  dbSNP: rs775583354
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000654601 SCV000776495 uncertain significance Multiple endocrine neoplasia, type 2 2023-11-14 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1067 of the RET protein (p.Pro1067Ser). This variant is present in population databases (rs775583354, gnomAD 0.02%). This missense change has been observed in individual(s) with unilateral renal agenesis (PMID: 18252215). ClinVar contains an entry for this variant (Variation ID: 543760). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RET function (PMID: 16227613, 18252215). 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.
Counsyl RCV000663067 SCV000786132 uncertain significance Multiple endocrine neoplasia type 2A 2018-03-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV001019124 SCV001180444 likely benign Hereditary cancer-predisposing syndrome 2022-04-15 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV002284419 SCV002574677 uncertain significance not provided 2022-08-29 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a stillborn fetus with unilateral renal agenesis (Skinner et al., 2008); Published functional studies are inconclusive: this variant appears to inactivate RET51 by preventing autophosphorylation in response to GDNF (Skinner et al., 2008); This variant is associated with the following publications: (PMID: 18252215, 24336963)
Fulgent Genetics, Fulgent Genetics RCV002507130 SCV002816704 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A 2021-12-16 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV002284419 SCV003816118 uncertain significance not provided 2021-09-15 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000654601 SCV004825906 uncertain significance Multiple endocrine neoplasia, type 2 2023-08-15 criteria provided, single submitter clinical testing

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