rs74315370
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_003000.3(SDHB):c.136C>T(p.Arg46Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,622 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. R46R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_003000.3 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.136C>T | p.Arg46Ter | stop_gained | 2/8 | ENST00000375499.8 | |
SDHB | NM_001407361.1 | c.136C>T | p.Arg46Ter | stop_gained | 2/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.136C>T | p.Arg46Ter | stop_gained | 2/8 | 1 | NM_003000.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251342Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135850
GnomAD4 exome AF: 0.00000890 AC: 13AN: 1461472Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727056
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74318
ClinVar
Submissions by phenotype
Paragangliomas 4 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 01, 2023 | This variant changes 1 nucleotide in exon 2 of the SDHB gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with pheochromocytoma/paraganglioma (PMID: 19075037, 19454582, 21348866, 21909610, 23797725, 27539324, 28944243, 30122763). This variant has been identified in 5/282738 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SDHB function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
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. - |
Hereditary pheochromocytoma-paraganglioma Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This variant changes 1 nucleotide in exon 2 of the SDHB gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with pheochromocytoma/paraganglioma (PMID: 19075037, 19454582, 21348866, 21909610, 23797725, 27539324, 28944243, 30122763). This variant has been identified in 5/282738 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SDHB function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 10, 2020 | The p.Arg46X variant in SDHB has been reported in 11 individuals with SDHB-associated tumors and segregated with disease in 5 affected individuals from 3 families (Ricketts 2008 PMID:18728283, Srirangalingam 2008 PMID:18419787, Ghayee 2009 PMID:19075037, Hensen 2012 PMID:21348866, Mason 2013 PMID:23797725, Pandit 2016 PMID:27539324, Richter 2019 PMID:30050099). It has also been identified in 0.014% (1/7218) of "Other" or 0.008% of Finnish (2/25082) chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 142763). This nonsense variant leads to a premature termination codon at position 46, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the SDHB gene is an established disease mechanism in autosomal dominant 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, PS4_Moderate, PM2_Supporting, PP1_Moderate - |
Pathogenic, no assertion criteria provided | research | Section on Medical Neuroendocrinolgy, National Institutes of Health | - | - - |
not provided Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 22, 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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20418362, 21348866, 27539324, 12618761, 18728283, 23797725, 16405730, 19075037, 18419787, 16912137, 18840642, 19454582, 16317055, 22517557, 17102084, 26916530, 28374168, 28204537, 28152038, 30050099, 30122763, 31851316, 29623478, 30694796, 32082649, 30871634, 31492822, 29625052, 32741965, 33087929, 30787465) - |
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change creates a premature translational stop signal (p.Arg46*) 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 (rs74315370, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with pheochromocytoma, paraganglioma, and renal cell carcinoma (PMID: 12618761, 16405730, 18728283, 21348866, 23797725). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142763). For these reasons, this variant has been classified as Pathogenic. - |
Gastrointestinal stromal tumor Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 27, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2022 | The p.R46* pathogenic mutation (also known as c.136C>T), located in coding exon 2 of the SDHB gene, results from a C to T substitution at nucleotide position 136. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation has been reported multiple times as a disease-causing mutation in patients with PGL-PCC or renal cell carcinoma (Benn DE et al. Oncogene. 2003 Mar;22:1358-64; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91:827-36; Brouwers FM et al. J. Clin. Endocrinol. Metab. 2006 Nov;91:4505-9; Srirangalingam U et al. Clin. Endocrinol. 2008 Oct;69:587-96; Ricketts C et al. J. Natl. Cancer Inst. 2008 Sep;100:1260-2; Ghayee HK et al. Endocr. Relat. Cancer. 2009 Mar;16:291-9; Bayley JP et al. BMC Med. Genet. 2006 Jan;7:1; Mason EF et al. Am. J. Surg. Pathol. 2013 Oct;37:1612-8; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175(4):311-23; Chew WHW et al. Mol Genet Genomic Med. 2017 Sep;5(5):602-607). 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. - |
SDHB-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Mar 28, 2024 | PVS1, PS4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at