ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1859G>A (p.Cys620Tyr) (rs77503355)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413879 SCV000490769 pathogenic not provided 2017-09-22 criteria provided, single submitter clinical testing This pathogenic variant is denoted RET c.1859G>A at the cDNA level, p.Cys620Tyr (C620Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). This variant has been reported in multiple cases of familial medullary thyroid carcinoma and pheochromocytoma, commonly described as fitting a MEN2A phenotype (Donis-Keller 1993, Karga 1998, Frank-Raue 2011, Boichard 2012). Functional studies in NIH 3T3 mouse fibroblast cell lines associated RET Cys620Tyr with abnormalities compared to wild type, including constitutive phosphorylation at position Y905, failure to respond to glial cell-line derived neurotrophic factor (GDNF), and transformative properties as evidenced by increased clonogenic efficiency (Carlomagno 1998, Orgiana 2004, Ercolino 2008). RET Cys620Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RET Cys620Tyr occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000413879 SCV000886049 pathogenic not provided 2017-09-29 criteria provided, single submitter clinical testing The RET c.1859G>A;p.Cys620Tyr variant is published in the medical literature in individuals with MEN2A (Donis-Keller 1993, Orgiana 2004). Additionally, variants in this codon are described as causative for MEN2A, but variants in this codon have a lower penetrance ( Wells 2015). The c.1859G>A;p.Cys620Tyr variant is listed in the ClinVar database (Variation ID: 13916), in the dbSNP variant database (rs77503355), but not in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The cysteine at this position is highly conserved and computational algorithms (AlignGVGD, PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as pathogenic. References: Donis-Keller H et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993 Jul;2(7):851-6. Orgiana G et al. A new germline RET mutation apparently devoid of transforming activity serendipitously discovered in a patient with atrophic autoimmune thyroiditis and primary ovarian failure. J Clin Endocrinol Metab. 2004 Oct;89(10):4810-6. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610.
Invitae RCV000021801 SCV000934750 pathogenic Multiple endocrine neoplasia, type 2 2018-12-01 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 620 of the RET protein (p.Cys620Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with medullary thyroid carcinoma (MTC) and pheochromocytoma (PMID: 20979234, 8797874, 18063059, 16322339, 18062802, 9820617, 16868135, 26556299) and has been observed to segregate with MTC in affected families (PMID: 20979234). ClinVar contains an entry for this variant (Variation ID: 13916). Experimental studies have shown that this missense change leads to constitutive dimerization and activation of the RET receptor tyrosine kinase (PMID: 15472167, 9012462). This variant disrupts the p.Cys620 amino acid residue in RET. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 7849720, 19826964, 18206480, 9384613, 24805091, 19336503, 9146685, 7874109), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014936 SCV000035192 pathogenic Multiple endocrine neoplasia, type 2a 2013-09-04 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000021801 SCV000042467 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. Youngest with MTC: 18 yr. In vitro studies: PMID 9230192. In the oldest reference, exon 10 was called exon 7. Additional references: PMID 9820617, 20979234, 18063059, 16868135 and 8797874.
Database of Curated Mutations (DoCM) RCV000014936 SCV000510547 likely pathogenic Multiple endocrine neoplasia, type 2a 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431330 SCV000510548 likely pathogenic Multiple endocrine neoplasia, type 2b 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441133 SCV000510549 likely pathogenic Multiple endocrine neoplasia, type 4 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420281 SCV000510550 likely pathogenic Medullary thyroid carcinoma 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428368 SCV000510551 likely pathogenic Multiple endocrine neoplasia, type 1 2016-05-13 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000678747 SCV000804919 pathogenic Hirschsprung disease 2009-04-30 no assertion criteria provided clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000014936 SCV000804920 pathogenic Multiple endocrine neoplasia, type 2a 2009-04-30 no assertion criteria provided clinical testing

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