rs587781720
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5
The NM_004168.4(SDHA):c.818C>T(p.Thr273Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T273A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004168.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.818C>T | p.Thr273Ile | missense_variant | 7/15 | ENST00000264932.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.818C>T | p.Thr273Ile | missense_variant | 7/15 | 1 | NM_004168.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152160Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251326Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135864
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461770Hom.: 0 Cov.: 57 AF XY: 0.00000275 AC XY: 2AN XY: 727196
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152160Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74336
ClinVar
Submissions by phenotype
Paragangliomas 5 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 18, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 24, 2023 | 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. - |
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 16, 2023 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 17, 2020 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at