ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.1127T>C (p.Leu376Pro)

gnomAD frequency: 0.00001  dbSNP: rs1433477205
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000821732 SCV000962501 uncertain significance Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 2024-01-29 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 376 of the SDHA protein (p.Leu376Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SDHA-related conditions. ClinVar contains an entry for this variant (Variation ID: 663781). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV001017412 SCV001178488 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-20 criteria provided, single submitter clinical testing The p.L376P variant (also known as c.1127T>C), located in coding exon 9 of the SDHA gene, results from a T to C substitution at nucleotide position 1127. The leucine at codon 376 is replaced by proline, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV001551721 SCV001772288 uncertain significance not provided 2022-08-09 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genetics and Molecular Pathology, SA Pathology RCV003447567 SCV004175621 uncertain significance Mitochondrial complex II deficiency, nuclear type 1 2022-12-30 criteria provided, single submitter clinical testing

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