rs1060503757
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_003000.3(SDHB):c.591del(p.Ser198AlafsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P197P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
SDHB
NM_003000.3 frameshift
NM_003000.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.601
Genes affected
SDHB (HGNC:10681): (succinate dehydrogenase complex iron sulfur subunit B) This tumor suppressor gene encodes the iron-sulfur protein subunit of the succinate dehydrogenase (SDH) enzyme complex which plays a critical role in mitochondria. The SDH enzyme complex is composed of four nuclear-encoded subunits. This enzyme complex converts succinate to fumarate which releases electrons as part of the citric acid cycle, and the enzyme complex additionally provides an attachment site for released electrons to be transferred to the oxidative phosphorylation pathway. The SDH enzyme complex plays a role in oxygen-related gene regulation through its conversion of succinate, which is an oxygen sensor that stabilizes the hypoxia-inducible factor 1 (HIF1) transcription factor. Sporadic and familial mutations in this gene result in paragangliomas, pheochromocytoma, and gastrointestinal stromal tumors, supporting a link between mitochondrial dysfunction and tumorigenesis. Mutations in this gene are also implicated in nuclear type 4 mitochondrial complex II deficiency. [provided by RefSeq, Jun 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-17024023-TG-T is Pathogenic according to our data. Variant chr1-17024023-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 412462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17024023-TG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.591del | p.Ser198AlafsTer22 | frameshift_variant | 6/8 | ENST00000375499.8 | |
SDHB | NM_001407361.1 | c.537del | p.Ser180AlafsTer22 | frameshift_variant | 6/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.591del | p.Ser198AlafsTer22 | frameshift_variant | 6/8 | 1 | NM_003000.3 | P1 | |
SDHB | ENST00000491274.6 | c.549del | p.Ser184AlafsTer22 | frameshift_variant | 6/8 | 5 | |||
SDHB | ENST00000463045.3 | c.420del | p.Ser141AlafsTer22 | frameshift_variant | 6/8 | 3 | |||
SDHB | ENST00000485515.5 | n.525del | non_coding_transcript_exon_variant | 6/7 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 23, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 14, 2016 | The c.591delC pathogenic mutation, located in coding exon 6 of the SDHB gene, results from a deletion of one nucleotide at position 591 causing a translational frameshift with a predicted alternate stop codon. This pathogenic alteration has been reported in several unrelated individuals diagnosed with paraganglioma or pheochromocytoma (Amar L et al. .J Clin. Oncol. 2005 Dec 1;23(34):8812-8; Fakhry N et al. Eur. Arch. Otorhinolaryngol. 2008 May;265(5):557-63; 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 or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 412462). This premature translational stop signal has been observed in individuals with paraganglioma-pheochromocytoma syndrome (PMID: 16314641, 16317055, 19454582, 22517554, 23072324). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser198Alafs*22) 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). - |
Paragangliomas 4 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2001 | - - |
Gastrointestinal stromal tumor Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
SDHB-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Jan 05, 2022 | The c.591del;p.(Ser198Alafs*22) is a null frameshift variant (NMD) in the SDHB gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 412462; PMID: 22517554; 19454582; 23072324; 16314641; 16317055) - PS4. This variant is not present in population databases (rs1060503757, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at