Submissions for variant NM_004168.4(SDHA):c.923C>T (p.Thr308Met)

gnomAD frequency: 0.00001  dbSNP: rs1457666982

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000560478	SCV000651469	likely pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 308 of the SDHA protein (p.Thr308Met). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with gastrointestinal stromal tumor, paragangliomas and/or pheochromocytomas (PMID: 28500238, 28546994; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 472416). 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	RCV000563497	SCV000664525	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-19	criteria provided, single submitter	clinical testing	The p.T308M variant (also known as c.923C>T), located in coding exon 8 of the SDHA gene, results from a C to T substitution at nucleotide position 923. The threonine at codon 308 is replaced by methionine, an amino acid with similar properties. The variant has been detected in multiple individuals with paraganglioma or gastrointestinal stromal tumor (Rattenberry E et al. J Clin Endocrinol Metab. 2013 Jul;98:E1248-56; Casey RT et al. Mol Genet Genomic Med. 2017 May;5:237-250; Tufton N et al. Endocr. Relat. Cancer. 2017 07;24:L43-L49; Ambry internal data). Based on internal structural analysis, T308M results in disruption of the succinate binding site (Huang LS et al. Biochim Biophys Acta. 2006 Jul;1757:1073-83; Huang LS et al. J Biol Chem. 2006 Mar;281:5965-72; Shimizu H et al. J Biochem. 2012 Jun;151:589-92). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237920	SCV002009951	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
“Giorgio Prodi” Cancer Research Center, University of Bologna	RCV001799682	SCV002026131	uncertain significance	Gastrointestinal stromal tumor	2021-10-01	criteria provided, single submitter	research
GeneDx	RCV003237920	SCV004170143	likely pathogenic	not provided	2023-04-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22577165, 35059314, 16935256, 29978154, 36980917, 23666964, 16371358, 30854332, 28500238, 27011036, 28546994)