rs876660642
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003000.3(SDHB):c.713del(p.Phe238SerfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. F238F) has been classified as Likely benign.
Frequency
Consequence
NM_003000.3 frameshift
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 | UniProt |
---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.713del | p.Phe238SerfsTer10 | frameshift_variant | 7/8 | ENST00000375499.8 | |
SDHB | NM_001407361.1 | c.659del | p.Phe220SerfsTer10 | frameshift_variant | 7/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.713del | p.Phe238SerfsTer10 | frameshift_variant | 7/8 | 1 | NM_003000.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251466Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135912
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461806Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727222
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 12, 2023 | This variant is also known as c.713delT (p.Phe238fs). This premature translational stop signal has been observed in individual(s) with paraganglioma-pheochromocytoma syndromes (PMID: 16317055, 19454582, 22517554, 28490599). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Phe238Serfs*10) in the SDHB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acid(s) of the SDHB protein. ClinVar contains an entry for this variant (Variation ID: 233795). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SDHB protein in which other variant(s) (p.Leu240Serfs*16) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. - |
Gastrointestinal stromal tumor Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 19, 2023 | _x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 29, 2019 | The c.713delT pathogenic mutation, located in coding exon 7 of the SDHB gene, results from a deletion of one nucleotide at nucleotide position 713, causing a translational frameshift with a predicted alternate stop codon (p.F238Sfs*10). This mutation has been identified in several individuals with paraganglioma (PGL) and/or pheochromocytoma (PCC) (Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91(3):827-36; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94(8):2817-27; Rijken JA et al. Clin. Genet. 2018 Jan;93:60-66). In addition, loss of heterozygosity at the SDHB locus was established in the tumor of a germline carrier of this mutation (Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94(8):2817-27). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. - |
Hereditary pheochromocytoma-paraganglioma Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | This variant deletes 1 nucleotide in exon 7 of the SDHB gene, creating a frameshift and premature translation stop signal in exon 7. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. This variant has been reported in individuals affected with hereditary paraganglioma-pheochromocytoma syndrome (PMID: 16317055, 19454582, 22517554, 28490599). Downstream truncations are known to be disease-causing (ClinVar variation ID: 12782, 412481, 201607, 421424). This variant has been identified in 1/251466 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at