ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1973A>G (p.His658Arg)

gnomAD frequency: 0.00001  dbSNP: rs1274484329
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000697806 SCV000826437 uncertain significance Multiple endocrine neoplasia, type 2 2022-11-18 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 575557). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 658 of the RET protein (p.His658Arg).
Ambry Genetics RCV002422542 SCV002721359 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-21 criteria provided, single submitter clinical testing The p.H658R variant (also known as c.1973A>G), located in coding exon 11 of the RET gene, results from an A to G substitution at nucleotide position 1973. The histidine at codon 658 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics RCV005046953 SCV005667498 uncertain significance Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A 2024-05-16 criteria provided, single submitter clinical testing

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