rs786203251
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_003000.3(SDHB):c.724C>T(p.Arg242Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,776 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R242H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003000.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.724C>T | p.Arg242Cys | missense_variant | 7/8 | ENST00000375499.8 | |
SDHB | NM_001407361.1 | c.670C>T | p.Arg224Cys | missense_variant | 7/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.724C>T | p.Arg242Cys | missense_variant | 7/8 | 1 | NM_003000.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461776Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727196
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2022 | Published functional studies demonstrate intermediate SDH activity (Panizza et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24606901, 26464466, 33087929, 22517554, 15235042, 30217213, 29386252, 23072324, 17102086, 19802898, 19351833, 19454582, 23175444) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2016 | - - |
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 29, 2023 | This missense change has been observed in individuals with hereditary paraganglioma or pheochromocytoma (PMID: 15235042, 17102086, 19351833, 19802898, 22517554). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 242 of the SDHB protein (p.Arg242Cys). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 186827). 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. This variant disrupts the p.Arg242 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12000816, 19351833, 20208144). 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 Pathogenic. - |
Paragangliomas 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 18, 2023 | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:19454582, 31194233, 17102086, 32035780, 30201732]. Functional studies indicate this variant impacts protein function [PMID: 26719882]. 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 | Jun 23, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 02, 2023 | The p.R242C pathogenic mutation (also known as c.724C>T), located in coding exon 7 of the SDHB gene, results from a C to T substitution at nucleotide position 724. The arginine at codon 242 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in numerous individuals with sporadic and familial paragangliomas/pheochromocytomas (Badenhop RF et al. J. Med. Genet. 2004 Jul;41(7):e99; Schiavi F et al. Ann. N. Y. Acad. Sci. 2006 Aug;1073:190-7; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug; 94(8):2817-27; Lefebvre S et al. Horm. Metab. Res. 2012 May;44(5):334-8; Jafri M et al. Clin. Endocrinol. (Oxf). 2013 Jun;78(6):898-906; Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394). A functional study utilizing a yeast growth assay classified this alteration as a "mildly impaired mutation" after finding that analogous yeast p.R242C mutants were able to partially rescue oxidative cell growth but had significantly decreased SDH enzyme activity (Panizza E et al. Hum. Mol. Genet. 2013 Feb; 22(4):804-15). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
SDHB-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 06, 2023 | The SDHB c.724C>T variant is predicted to result in the amino acid substitution p.Arg242Cys. This variant has been reported in multiple individuals with pheochromocytoma or paraganglioma (Lefebvre et al. 2012. PubMed ID: 22517554; Table S2, Garrett et al. 2022. PubMed ID: 34906457; Kim et al. 2022. PubMed ID: 33219105). Functional studies in yeast found this variant has a mild impact on SDHB function (Panizza et al. 2013. PubMed ID: 23175444). This variant has not been reported in a large population database, indicating this variant is rare. Additionally, different missense variants (p.Arg242His, p.Arg242Ser) affecting this amino acid have been documented as pathogenic (Table S2, Garrett et al. 2022. PubMed ID: 34906457). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at