ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.3G>A (p.Met1Ile) (rs80338842)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000703383 SCV000832280 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2019-06-17 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the SDHD mRNA. The next in-frame methionine is located at codon 91. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with head and neck paraganglioma (HNPGL) and pheochromocytoma (PCC) (PMID: 19258401). In addition, different changes at the initiator codon (c.1A>G, c.2T>A, c.2T>C, and c.3G>C) have also been observed in individuals and families with HNPGLs or other SDHD-related tumors, and have been shown to segregate with disease in the affected families (PMID: 11391796, 15066320, 21945342, 19454582, 19351833, 17576205, 22241717). While this variant is expected to result in an absent protein product, possible rescue of translational initiation by the downstream methionine would lead to the loss of ~60% of the SDHD protein, including the signal peptide domain required for entering the mitochondrial membrane (PMID: 12612654, 15066320). For these reasons, this variant has been classified as Pathogenic.

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