ClinVar Miner

Submissions for variant NM_003002.4(SDHD):c.320T>G (p.Leu107Arg) (rs876658477)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219575 SCV000273754 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-10 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000460873 SCV000554059 likely pathogenic Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas 1; Cowden syndrome 3 2019-10-21 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 107 of the SDHD protein (p.Leu107Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with head and neck paraganglioma and has been observed to segregate with head and neck paraganglioma in a single family (Invitae). ClinVar contains an entry for this variant (Variation ID: 230274). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The observation of one or more missense substitutions at this codon (p.Leu107Pro) in affected individuals suggests that this may be a clinically significant residue (PMID: 28977582). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000986022 SCV001134819 likely pathogenic not provided 2019-02-27 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Enriched in patients. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid.

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