rs74315366
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_003000.3(SDHB):c.268C>T(p.Arg90Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000434 in 1,613,230 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R90R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_003000.3 stop_gained
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.268C>T | p.Arg90Ter | stop_gained | 3/8 | ENST00000375499.8 | |
SDHB | NM_001407361.1 | c.268C>T | p.Arg90Ter | stop_gained | 3/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.268C>T | p.Arg90Ter | stop_gained | 3/8 | 1 | NM_003000.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251336Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135842
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460972Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726836
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152258Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74442
ClinVar
Submissions by phenotype
Paragangliomas 4 Pathogenic:5
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2001 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 08, 2024 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | May 27, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | UCLA Clinical Genomics Center, UCLA | Jan 21, 2014 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 18, 2021 | This nonsense variant causes the premature termination of SDHB protein synthesis. In the published literature, the variant has been reported in individuals with paraganglioma, pheochromocytoma, gastrointestinal stromal tumor, and renal cell carcinoma (PMIDs: 28374168 (2017), 28324028 (2017), 23083876 (2012), 19454582 (2009), 18419787 (2008), and 11404820 (2001)). Therefore, the variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 10, 2021 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(R62*); This variant is associated with the following publications: (PMID: 26332594, 27573198, 17102068, 20061288, 25371406, 27171833, 16314641, 18419787, 25972245, 25525159, 22517557, 11404820, 28324028, 26230854, 21934479, 26464466, 23083876, 28374168, 19454582, 28973655, 15328326, 19576851, 12618761, 16317055, 24659481, 28748451, 30050099, 31666924, 31492822, 32804377, 32741965, 30787465, 33726816) - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Hereditary pheochromocytoma-paraganglioma Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 17, 2022 | Variant summary: SDHB c.268C>T (p.Arg90X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251336 control chromosomes (gnomAD). c.268C>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (e.g. Astuti_2001, Benn_2006, Andrews_2018). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant has no protein activity (Kim_2015). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 21, 2019 | The p.Arg90X variant in SDHB has previously been identified in at least 12 individuals with SDHB-associated tumors and segregated with disease in 9 affected family members from at least 5 families (Amar 2005, Zu 2011, Srirangalingam 2008, Benn 2006, Hensen 2012, Elston 2017, Gill 2011, Lee 2014, Crona 2014, Burnichon 2009, Benn 2003). It has also been identified in 2/113664 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 12778). This nonsense variant leads to a premature termination codon at position 90, which is predicted to lead to a truncated or absent protein. Functional studies support an impact on protein function (Kim 2015, Elston 2017). Heterozygous loss of function of the SDHB gene is an established disease mechanism in patients with hereditary paraganglioma and pheochromocytoma. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary paraganglioma and pheochromocytoma. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate, PS3_Supporting. - |
Pathogenic, no assertion criteria provided | research | Section on Medical Neuroendocrinolgy, National Institutes of Health | - | - - |
Von Hippel-Lindau syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS) | May 10, 2023 | - - |
Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1861848:Paragangliomas 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This sequence change creates a premature translational stop signal (p.Arg90*) in the SDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). This variant is present in population databases (rs74315366, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with pheochromocytoma, paraganglioma and renal cell carcinoma (PMID: 11404820, 12618761, 16314641, 16317055, 18419787, 19454582, 21348866, 21934479, 23083876, 24466223, 25326637). This variant is also known as R91X. ClinVar contains an entry for this variant (Variation ID: 12778). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 05, 2024 | The p.R90* pathogenic mutation (also known as c.268C>T), located in coding exon 3 of the SDHB gene, results from a C to T substitution at nucleotide position 268. This changes the amino acid from an arginine to a stop codon within coding exon 3. This pathogenic mutation has been reported in multiple unrelated families exhibiting pheochromocytomas and/or paragangliomas (Astuti D et al. Am J Hum Genet. 2001 Jul;69(1):49-54; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91:827-36; Ricketts CJ et al. J Urol. 2012 Dec;188(6):2063-71; Crona J et al. PLoS One. 2014 Jan;9(1):e86756; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143(8):1421-1435; Albattal S et al. Oncotarget. 2019 Oct 15;10(57):5919-5931). This mutation has also been identified in a woman with a renal tumor and family history of paragangliomas, where the renal tumor demonstrated negative SDHB staining by immunohistochemistry (Gill AJ et al. Am. J. Surg. Pathol. 2011 Oct;35:1578-85). It was recently seen in a patient with a duodenal GIST who also had a family history of paragangliomas. IHC analysis of the GIST showed negative SDHB staining, and the tumor was positive for the p.R90* mutation (Elston MS et al. J. Clin. Endocrinol. Metab. 2017 May;102(5):1447-1450). In vitro data showed complete loss of SDHB expression in cytosolic and mitochondrial compartments as well as no measurable SDH activity in cells transfected with this truncating mutation (Kim E et al. Endocr. Relat. Cancer 2015 Jun;22:387-97). Of note, this mutation is referred to as p.R91X in the Astuti (2001) paper. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at