ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.1532T>C (p.Leu511Pro) (rs375194444)

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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 RCV000571145 SCV000674925 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000484270 SCV000565543 uncertain significance not provided 2018-07-19 criteria provided, single submitter clinical testing The L511P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The L511P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L511P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Leucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000225792 SCV000288115 uncertain significance Mitochondrial complex II deficiency; Paragangliomas 5 2018-12-31 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 511 of the SDHA protein (p.Leu511Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs375194444, ExAC 0.01%). This variant has not been reported in the literature in individuals with a SDHA-related disease. ClinVar contains an entry for this variant (Variation ID: 239650). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on SDHA function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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