ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.1A>G (p.Met1Val) (rs104894307)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000471388 SCV000554046 pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 2019-07-25 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the SDHD mRNA. An alternate in-frame methionine downstream of the initiator codon is located at codon 91, which could potentially rescue translational initiation. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals and a family with head and neck paragangliomas (HNPGLs) (PMID: 15066320, 21945342). In addition, different changes at the initiator codon (c.2T>A, c.2T>C, and c.3G>C) have also been observed in individuals and families with HNPGLs or non-HNPGLs, and have been shown to segregate with disease in the affected families (PMID: 11391796, 21945342, 19454582, 19351833, 17576205, 22241717). ClinVar contains an entry for this variant (Variation ID: 6911). 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, which contains the signal peptide domain required for entering into the mitochondrial membrane (PMID: 12612654, 15066320). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000007320 SCV000027518 pathogenic Carotid body paraganglioma 2004-04-15 no assertion criteria provided literature only

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