ClinVar Miner

Submissions for variant NM_024529.4(CDC73):c.1A>G (p.Met1Val) (rs1558276054)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000706820 SCV000835893 likely pathogenic Parathyroid carcinoma 2018-04-13 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the CDC73 mRNA. The next in-frame methionine is located at codon 177. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CDC73-related disease. 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. This variant at the initiator codon is expected to affect translation initiation. Rescue of translation at the next in-frame methionine at codon 177 may result in N-terminal truncation missing the nuclear localization signal (NLS) (residues 125-139) (PMID: 17314275, 16116486). This suggests that translation initiation at the methionine residue at codon 1 is critical for proper localization and function of the CDC73 protein. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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