Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000559654 | SCV000651372 | likely pathogenic | Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 | 2024-01-16 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 445 of the SDHA protein (p.Ser445Leu). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with gastrointestinal stromal tumor, paraganglioma, and/or pheochromocytoma (PMID: 28384794, 29527294, 30854332; Invitae). ClinVar contains an entry for this variant (Variation ID: 472322). 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 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. |
| Ambry Genetics | RCV001011108 | SCV001171391 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-07-03 | criteria provided, single submitter | clinical testing | The p.S445L variant (also known as c.1334C>T), located in coding exon 10 of the SDHA gene, results from a C to T substitution at nucleotide position 1334. The serine at codon 445 is replaced by leucine, an amino acid with dissimilar properties. This variant has been reported in the germline of patients with paragangliomas (Currás-Freixes M et al. J Mol Diagn. 2017 07;19:575-588; Bausch B et al. JAMA Oncol. 2017 Sep;3:1204-1212; Bernardo-Castiñeira C et al. Head Neck. 2019 Jan;41:79-91; Díaz-Castellanos MA et al. F1000Res, 2017 Dec;6:2087; Ma X et al. Front Endocrinol (Lausanne), 2020 Dec;11:574662). It has also been reported as a somatic finding in gastrointestinal stromal tumors (Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40; Boikos SA et al. JAMA Oncol. 2016 Jul;2:922-8; Dubard Gault M et al. Cold Spring Harb Mol Case Stud. 2018 08;4:). In one reported case, this variant was seen as a somatic finding in a patient with a germline SDHA p.R31* alteration (Dubard Gault M et al. Cold Spring Harb Mol Case Stud. 2018 08;4:). Based on internal structural analysis, S445L decreases the structure stability (Inaoka DK et al. Int J Mol Sci 2015 Jul;16(7):15287-308) This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Institute for Clinical Genetics, |
RCV003237919 | SCV002009966 | uncertain significance | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003476307 | SCV004200618 | uncertain significance | Dilated cardiomyopathy 1GG | 2023-07-20 | criteria provided, single submitter | clinical testing |