1-17028727-C-T
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_003000.3(SDHB):c.296G>A(p.Gly99Asp) 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. G99S) has been classified as Uncertain significance.
Frequency
Consequence
NM_003000.3 missense
Scores
Clinical Significance
Conservation
Publications
- Carney-Stratakis syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
- gastrointestinal stromal tumorInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- pheochromocytomaInheritance: AD Classification: DEFINITIVE Submitted by: G2P
- pheochromocytoma/paraganglioma syndrome 4Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- mitochondrial diseaseInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- renal cell carcinomaInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- mitochondrial complex 2 deficiency, nuclear type 4Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Cowden diseaseInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- mitochondrial complex II deficiencyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
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; Observed in individuals with paraganglioma and/or pheochromocytoma (Benn et al., 2006; Andrews et al., 2018; Bayley et al., 2020); This variant is associated with the following publications: (PMID: 15989954, 16317055, 29386252, 33162331, 19802898, 25972245, 19215943, 31492822, 29315604) -
Pheochromocytoma/paraganglioma syndrome 4 Pathogenic:1
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Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 Pathogenic:1
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 99 of the SDHB protein (p.Gly99Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paraganglioma and/or pheochromocytoma (PMID: 16317055, 31492822; internal data). ClinVar contains an entry for this variant (Variation ID: 239428). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.G99D variant (also known as c.296G>A), located in coding exon 4 of the SDHB gene, results from a G to A substitution at nucleotide position 296. The glycine at codon 99 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been identified in multiple individuals with personal and/or family history of paraganglioma and/or pheochromocytoma (Benn DE et al. J Clin Endocrinol Metab, 2006 Mar;91:827-36; Andrews KA et al. J Med Genet, 2018 06;55:384-394; Bayley JP et al. J Med Genet, 2020 02;57:96-103). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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