rs763766162
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_004168.4(SDHA):c.1766G>A(p.Arg589Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R589W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004168.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1766G>A | p.Arg589Gln | missense_variant | 13/15 | ENST00000264932.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1766G>A | p.Arg589Gln | missense_variant | 13/15 | 1 | NM_004168.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000274 AC: 4AN: 1461640Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727126
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 589 of the SDHA protein (p.Arg589Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with gastrointestinal stromal tumors and paraganglioma-pheochromocytoma syndromes (PMID: 23612575, 25720320, 28384794). ClinVar contains an entry for this variant (Variation ID: 412342). 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. This variant disrupts the p.Arg589 amino acid residue in SDHA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20484225, 22955521, 25405498, 28546994). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Dilated cardiomyopathy 1GG Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 17, 2023 | - - |
Gastrointestinal stromal tumor Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | “Giorgio Prodi” Cancer Research Center, University of Bologna | Oct 01, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 18, 2023 | The p.R589Q variant (also known as c.1766G>A), located in coding exon 13 of the SDHA gene, results from a G to A substitution at nucleotide position 1766. The arginine at codon 589 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in individuals with a history of paraganglioma/pheochromocytoma (Papathomas TG et al. Mod Pathol, 2015 Jun;28:807-21; Bausch B et al. JAMA Oncol, 2017 Sep;3:1204-1212), as well as an individual with a gastrointestinal stromal tumor (GIST) that showed loss of SDHA by immunohistochemistry (IHC) (Pantaleo MA et al. Eur J Hum Genet, 2014 Jan;22:32-9; Pantaleo MA et al. Front Oncol, 2021 Jan;11:778461). Based on internal structural analysis, p.R589Q disrupt the structural stability (Ambry internal data). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at