chr5-233504-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_004168.4(SDHA):c.923C>T(p.Thr308Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,998 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. T308A) has been classified as Uncertain significance.
Frequency
Consequence
NM_004168.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHA | NM_004168.4 | c.923C>T | p.Thr308Met | missense_variant | 8/15 | ENST00000264932.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHA | ENST00000264932.11 | c.923C>T | p.Thr308Met | missense_variant | 8/15 | 1 | NM_004168.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251494Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135920
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461840Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727220
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152158Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74336
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 20, 2023 | 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: 22577165, 35059314, 16935256, 29978154, 36980917, 23666964, 16371358, 30854332, 28500238, 27011036, 28546994) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Paragangliomas 5;C5700310:Mitochondrial complex II deficiency, nuclear type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 28, 2023 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 308 of the SDHA protein (p.Thr308Met). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with gastrointestinal stromal tumor, paragangliomas and/or pheochromocytomas (PMID: 28500238, 28546994; Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 472416). 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 | Jan 19, 2024 | The p.T308M variant (also known as c.923C>T), located in coding exon 8 of the SDHA gene, results from a C to T substitution at nucleotide position 923. The threonine at codon 308 is replaced by methionine, an amino acid with similar properties. The variant has been detected in multiple individuals with paraganglioma or gastrointestinal stromal tumor (Rattenberry E et al. J Clin Endocrinol Metab. 2013 Jul;98:E1248-56; Casey RT et al. Mol Genet Genomic Med. 2017 May;5:237-250; Tufton N et al. Endocr. Relat. Cancer. 2017 07;24:L43-L49; Ambry internal data). Based on internal structural analysis, T308M results in disruption of the succinate binding site (Huang LS et al. Biochim Biophys Acta. 2006 Jul;1757:1073-83; Huang LS et al. J Biol Chem. 2006 Mar;281:5965-72; Shimizu H et al. J Biochem. 2012 Jun;151:589-92). 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