ClinVar Miner

Submissions for variant NM_020975.6(RET):c.961G>A (p.Gly321Arg) (rs377767388)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148776 SCV000190513 uncertain significance Medullary thyroid carcinoma 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
Invitae RCV000231209 SCV000290569 uncertain significance Multiple endocrine neoplasia, type 2 2018-09-10 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 321 of the RET protein (p.Gly321Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs377767388, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in a single family affected with medullary thyroid carcinoma and/or C-cell hyperplasia. However, the variant did not segregate with disease in this family (PMID: 16419493). ClinVar contains an entry for this variant (Variation ID: 24881). 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, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Ambry Genetics RCV000567555 SCV000674744 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
PreventionGenetics,PreventionGenetics RCV000679758 SCV000807066 uncertain significance not provided 2018-01-17 criteria provided, single submitter clinical testing
Mendelics RCV000709104 SCV000838373 uncertain significance Multiple endocrine neoplasia, type 2a 2018-07-02 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV000021762 SCV000042428 uncertain significance not specified 2018-05-04 no assertion criteria provided literature only Single Czech family report, 4 have the variant genotype: 1 metastatic MTC (61 yr), 1 bi-lateral C-cell hyperplasia (42 yr).

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