rs786202732
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The ENST00000375499.8(SDHB):āc.574T>Cā(p.Cys192Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,668 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 Pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C192S) has been classified as Likely pathogenic.
Frequency
Consequence
ENST00000375499.8 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.574T>C | p.Cys192Arg | missense_variant | 6/8 | ENST00000375499.8 | NP_002991.2 | |
SDHB | NM_001407361.1 | c.520T>C | p.Cys174Arg | missense_variant | 6/8 | NP_001394290.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.574T>C | p.Cys192Arg | missense_variant | 6/8 | 1 | NM_003000.3 | ENSP00000364649 | P1 | |
SDHB | ENST00000491274.6 | c.532T>C | p.Cys178Arg | missense_variant | 6/8 | 5 | ENSP00000480482 | |||
SDHB | ENST00000463045.3 | c.403T>C | p.Cys135Arg | missense_variant | 6/8 | 3 | ENSP00000481376 | |||
SDHB | ENST00000485515.5 | n.508T>C | non_coding_transcript_exon_variant | 6/7 | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461668Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727122
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 31, 2023 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 192 of the SDHB protein (p.Cys192Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paragangliomas and/or pheochromocytomas many of them were classified as malignant (PMID: 12000816, 17200167, 18382370, 22517554, 25371406, 27785149). ClinVar contains an entry for this variant (Variation ID: 186150). 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 expected to disrupt SDHB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 22835832). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 04, 2016 | This pathogenic variant is denoted SDHB c.574T>C at the cDNA level, p.Cys192Arg (C192R) at the protein level, and results in the change of a Cysteine to an Arginine (TGT>CGT). This variant has been reported in numerous individuals with parangangliomas or pheochromocytomas, many of which were metastatic (Neumann 2002, Timmers 2007, Burnichon 2009, Hensen 2012, Lefebvre 2012, Michalowska 2015, Sue 2015). SDHB Cys192Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. SDHB Cys192Arg occurs at a position that is conserved across species and is located in the 4Fe-4S ferredoxin-type domain (Uniprot). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic. - |
Paragangliomas 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 08, 2023 | This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:33628464, 30050099, 27867439, 28503760]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
Gastrointestinal stromal tumor Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 06, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 19, 2022 | The p.C192R pathogenic mutation (also known as c.574T>C), located in coding exon 6 of the SDHB gene, results from a T to C substitution at nucleotide position 574. The cysteine at codon 192 is replaced by arginine, an amino acid with highly dissimilar properties.This alteration has been identified in numerous individuals with paragangliomas and pheochromocytomas (Neumann HP et al. N. Engl. J. Med. 2002 May;346(19):1459-66; Lefebvre S et al. Horm. Metab. Res. 2012 May;44(5):334-8; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94(8):2817-27; Klein RD et al. Diagn. Mol. Pathol. 2008 Jun;17(2):94-100; Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar; 92(3):779-86; Michaowska I et al. Kardiochir Torakochirurgia Pol, 2016 Sep;13:276-282). In one series of functional studies, the SDHB p.C192R mutant protein was subject to premature degradation, possibly due to the increased ubiquitination levels observed in the mutant protein compared to wild type SDHB protein (Yang C et al. FASEB J. 2012 Nov;26(11):4506-16). The Cys192 residue plays a vital role coordinating the Fe4S4 cluster and it is believed that alterations at this location would prevent assembly of Complex II (Iverson TM et al. J. Biol. Chem. 2012 Oct;287(42):35430-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Hereditary pheochromocytoma-paraganglioma Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Section on Medical Neuroendocrinolgy, National Institutes of Health | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at