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

gnomAD frequency: 0.00001  dbSNP: rs587781720

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129906	SCV000184724	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-07-04	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 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000649428	SCV000771256	likely pathogenic	Mitochondrial complex II deficiency, nuclear type 1; Paragangliomas 5	2024-09-27	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; external communication, internal data). ClinVar contains an entry for this variant (Variation ID: 141401). Invitae Evidence 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 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.
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV004719709	SCV005324800	likely pathogenic	Neoplasm of brain		criteria provided, single submitter	clinical testing	This sequence change, c.818C>T, in exon 7 of SDHA gene results in the missense change, p.Thr273Ile. This variant is present in population databases (rs587781720, gnomAD 0.003%). This change has been observed in individuals with GIST (PMID: 23109135, 27011036). ClinVar contains an entry for this variant (Variation ID: 141401). c paraganglioma tumor, diagnosed in a 57-year-old male. This amino acid position is highly conserved in available vertebrate species. In addition, this change is predicted to be deleterious by in silico analysis. For these reasons, this variant has been classified as Likely Pathogenic.
GeneDx	RCV005222762	SCV005870279	uncertain significance	not provided	2024-08-18	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: 28748451, 23730622, 25394176, 23282968, 24886695, 27986441, 23109135, 36980917, 32741965, 27011036)