ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2522C>T (p.Pro841Leu) (rs149891333)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000575365 SCV000664576 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-26 criteria provided, single submitter clinical testing Insufficient evidence
Counsyl RCV000662511 SCV000785050 uncertain significance Multiple endocrine neoplasia, type 2a 2017-03-30 criteria provided, single submitter clinical testing
Invitae RCV000691895 SCV000819693 uncertain significance Multiple endocrine neoplasia, type 2 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 841 of the RET protein (p.Pro841Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs149891333, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals affected with clinical features of multiple endocrine neoplasia type 2 or Hirschsprung's disease (PMID: 26071011, 22648184, 24134185). ClinVar contains an entry for this variant (Variation ID: 24947). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000763647 SCV000894527 uncertain significance Congenital central hypoventilation; Hirschsprung disease 1; Multiple endocrine neoplasia, type 2b; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia, type 2a 2018-10-31 criteria provided, single submitter clinical testing
Gharavi Laboratory,Columbia University RCV000782197 SCV000920670 uncertain significance not provided 2018-09-16 criteria provided, single submitter research
Research and Development, ARUP Laboratories RCV000021861 SCV000042527 uncertain significance not specified 2018-05-04 no assertion criteria provided literature only First report, single individual: MTC only. Patient had unilateral MTC and no family history of MEN2. Second report, single Korean individual: Pheo only at 42 yr (PMID 24134185). Variant was also found in a HSCR patient (PMID 12566528).
CSER _CC_NCGL, University of Washington RCV000148778 SCV000190516 uncertain significance Hirschsprung disease 2014-06-01 no assertion criteria provided research

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