rs1553178729
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The ENST00000375499.8(SDHB):c.190del(p.Asp64ThrfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
SDHB
ENST00000375499.8 frameshift
ENST00000375499.8 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.14
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 12 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 1-17044770-TC-T is Pathogenic according to our data. Variant chr1-17044770-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 468233.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.190del | p.Asp64ThrfsTer13 | frameshift_variant | 2/8 | ENST00000375499.8 | NP_002991.2 | |
SDHB | NM_001407361.1 | c.190del | p.Asp64ThrfsTer13 | frameshift_variant | 2/8 | NP_001394290.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.190del | p.Asp64ThrfsTer13 | frameshift_variant | 2/8 | 1 | NM_003000.3 | ENSP00000364649 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 27, 2023 | This sequence change creates a premature translational stop signal (p.Asp64Thrfs*13) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pheochromocytoma or paraganglioma (PMID: 23154831). ClinVar contains an entry for this variant (Variation ID: 468233). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Splicing
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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