ClinVar Miner

Submissions for variant NM_020975.6(RET):c.3116C>T (p.Pro1039Leu)

gnomAD frequency: 0.00004  dbSNP: rs79853121
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410425 SCV000489779 uncertain significance Multiple endocrine neoplasia type 2B 2016-02-02 criteria provided, single submitter clinical testing
Counsyl RCV000411688 SCV000489780 uncertain significance Multiple endocrine neoplasia type 2A 2016-02-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000563865 SCV000674898 likely benign Hereditary cancer-predisposing syndrome 2022-03-04 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000704911 SCV000833884 uncertain significance Multiple endocrine neoplasia, type 2 2023-12-26 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1039 of the RET protein (p.Pro1039Leu). This variant is present in population databases (rs79853121, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital central hypoventilation syndrome and total colonic aganglionosis (PMID: 9497256). ClinVar contains an entry for this variant (Variation ID: 13948). 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: 9502784, 10921886). 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.
Fulgent Genetics, Fulgent Genetics RCV002490367 SCV002802047 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A 2022-04-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003398513 SCV004122829 uncertain significance not specified 2023-10-12 criteria provided, single submitter clinical testing Variant summary: RET c.3116C>T (p.Pro1039Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251464 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3116C>T has been reported in the literature in an individual affected with total colonic aganglionosis (Amiel_1998) . This report does not provide unequivocal conclusions about association of the variant with Multiple Endocrine Neoplasia Type 2. At least one publication reports experimental evidence evaluating an impact on protein function (Pelet_1998). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 25637381, 9497256, 9502784). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=1) and VUS (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV000014975 SCV005054186 uncertain significance Hirschsprung disease, susceptibility to, 1 2024-02-23 criteria provided, single submitter clinical testing
OMIM RCV000014975 SCV000035231 risk factor Hirschsprung disease, susceptibility to, 1 1998-03-01 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000148783 SCV000190521 uncertain significance Aganglionic megacolon 2014-06-01 no assertion criteria provided research

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