rs771111180
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong
The NM_004168.4(SDHA):c.1741G>A(p.Gly581Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,613,794 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G581E) has been classified as Uncertain significance.
Frequency
Consequence
NM_004168.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.1741G>A | p.Gly581Arg | missense_variant | 13/15 | ENST00000264932.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.1741G>A | p.Gly581Arg | missense_variant | 13/15 | 1 | NM_004168.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250956Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135682
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461650Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727134
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328
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 | Oct 28, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 581 of the SDHA protein (p.Gly581Arg). This variant is present in population databases (rs771111180, gnomAD 0.0009%). This missense change has been observed in individuals with paraganglioma (PMID: 30877234; Invitae). ClinVar contains an entry for this variant (Variation ID: 571817). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SDHA protein function with a negative predictive value of 95%. 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. - |
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 | Feb 16, 2023 | The p.G581R variant (also known as c.1741G>A), located in coding exon 13 of the SDHA gene, results from a G to A substitution at nucleotide position 1741. The glycine at codon 581 is replaced by arginine, an amino acid with dissimilar properties. This variant was identified in one individual with head and neck paraganglioma; immunohistochemistry (IHC) of the tumor revealed absent SDHA and SDHB (Ben Aim L et al. J Med Genet, 2019 Aug;56:513-520). This variant was also detected with another SDHA pathogenic variant in gastrointestinal stromal tumor, which showed negative SDHB on IHC (Pantaleo MA et al. Front Oncol, 2021 Jan;11:778461). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on internal structural analysis, this variant is highly destabilizing to the local structure. This amino acid position is well 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