rs752360961
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP3_StrongPP5
The NM_004168.4(SDHA):c.1754G>A(p.Arg585Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R585W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_004168.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1754G>A | p.Arg585Gln | missense_variant | 13/15 | ENST00000264932.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1754G>A | p.Arg585Gln | missense_variant | 13/15 | 1 | NM_004168.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250992Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135688
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461648Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727132
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152186Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74362
ClinVar
Submissions by phenotype
Paragangliomas 5 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 23, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | May 03, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 585 of the SDHA protein (p.Arg585Gln). This variant is present in population databases (rs752360961, gnomAD 0.003%) also not present in our local database . This amino acid position is highly conserved (PhyloP= 8.84). This missense change has been observed in individuals with paragangliomas and pheochromocytomas or gastrointestinal stromal tumor (PMID: 26269449, 30877234). ClinVar contains an entry for this variant (Variation ID: 239658). In addition, this alteration is predicted to be deleterious by in silico analysis. This variant disrupts the p.Arg585 amino acid residue in SDHA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25720320, 29177515). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Likely Pathogenic. A heterozygous mutation in SDHA gene (MIM*600857) associated with neurodegenerative with ataxia and late onset of optic atrophy (MIM#619259) and Paragangliomas 5 (MIM#614165) also associated SDHA-deficient GIST . - |
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 27, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg585 amino acid residue in SDHA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25720320, 29177515). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 239658). This missense change has been observed in individuals with paragangliomas and pheochromocytomas or gastrointestinal stromal tumor (PMID: 26269449, 30877234; Invitae). This variant is present in population databases (rs752360961, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 585 of the SDHA protein (p.Arg585Gln). - |
Paragangliomas 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.1754G>A p.Arg585Gln in the SDHA gene has been reported previously in patients affected with Pheochromocytoma and Paraganglioma Ben Aim et al., 2019; van der Tuin et al., 2018. This variant is reported with the allele frequency 0.0007% in the gnomAD Exomes and novel not in any individuals in 1000 Genomes. It is submitted to ClinVar as Pathogenic/ Likely pathogenic/ Uncertain significance. However functional evidence on teh pathogenicity of teh variant is unavailable. The amino acid Arginine at position 585 is changed to a Glutamine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. - |
Dilated cardiomyopathy 1GG Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 01, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 07, 2023 | The p.R585Q variant (also known as c.1754G>A), located in coding exon 13 of the SDHA gene, results from a G to A substitution at nucleotide position 1754. The arginine at codon 585 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in multiple individuals with paraganglioma or pheochromocytoma (Currás-Freixes M et al. J Med Genet, 2015 Oct;52:647-56; Ben Aim L et al. J Med Genet, 2019 08;56:513-520; Ambry internal data). This alteration has also been reported in an individual with a personal history of a gastrointestinal stromal tumor (GIST) with loss of SDHB on IHC (Pantaleo MA et al. Front Oncol, 2021 Jan;11:778461). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Inaoka DK et al. Int J Mol Sci, 2015 Jul;16:15287-308). 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. - |
Gastrointestinal stromal tumor Uncertain:1
Uncertain significance, criteria provided, single submitter | research | “Giorgio Prodi” Cancer Research Center, University of Bologna | Oct 01, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at