ClinVar Miner

Submissions for variant NM_004168.4(SDHA):c.818C>T (p.Thr273Ile)

gnomAD frequency: 0.00001  dbSNP: rs587781720
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129906 SCV000184724 likely pathogenic Hereditary cancer-predisposing syndrome 2023-05-16 criteria provided, single submitter clinical testing The p.T273I variant (also known as c.818C>T), located in coding exon 7 of the SDHA gene, results from a C to T substitution at nucleotide position 818. The threonine at codon 273 is replaced by isoleucine, an amino acid with similar properties. This alteration has been previously identified as a somatic finding in several gastrointestinal stromal tumors (GISTs) demonstrating absence of SDHB and presence of SDHA protein staining by IHC (Belinsky MG et al. Genes Chromosomes Cancer. 2013 Feb;52:214-24; Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40; Boikos SA et al. JAMA Oncol. 2016 Jul;2:922-8). Two of these individuals diagnosed with GIST were also found to carry this alteration in germline DNA (Belinsky MG et al. Genes Chromosomes Cancer. 2013 Feb;52:214-24; Boikos SA et al. JAMA Oncol. 2016 Jul;2:922-8), while no germline specimen was available for the third case (Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40). This alteration has also been reported as a somatic finding in a sporadic paraganglioma tumor, diagnosed in a 57-year-old male. No germline alterations were reported in this individual (Pillai S et al. Exp. Mol. Pathol. 2017 02;102:41-46). 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.
Counsyl RCV000409578 SCV000488301 uncertain significance Paragangliomas 5 2016-02-18 criteria provided, single submitter clinical testing
Invitae RCV000649428 SCV000771256 likely pathogenic Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5 2024-01-12 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 273 of the SDHA protein (p.Thr273Ile). This variant is present in population databases (rs587781720, gnomAD 0.003%). This missense change has been observed in individuals with gastrointestinal stromal tumor, pheochromocytoma and paraganglioma (PMID: 23109135, 27011036; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 141401). 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.
Genetic Services Laboratory, University of Chicago RCV001818307 SCV002067440 uncertain significance not specified 2020-02-17 criteria provided, single submitter clinical testing DNA sequence analysis of the SDHA gene demonstrated a sequence change, c.818C>T, in exon 7 that results in an amino acid change, p.Thr273Ile. This sequence change has been described in the gnomAD database in three individuals (dbSNPrs587781720). The p.Thr273Ile change has been reported in an individual with gastrointestinal stromal tumor (PMID: 23109135). The p.Thr273Ile change affects a highly conserved amino acid residue located in a domain of the SDHA protein that is known to be functional. The p.Thr273Ile substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Thr273Ile change remains unknown at this time.
Myriad Genetics, Inc. RCV000409578 SCV004045366 uncertain significance Paragangliomas 5 2023-04-24 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

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