rs1553179359
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003000.3(SDHB):c.21del(p.Ser8ProfsTer2) variant causes a frameshift change. 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. L7L) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 31)
Consequence
SDHB
NM_003000.3 frameshift
NM_003000.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.67
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 does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 301 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-17053998-AG-A is Pathogenic according to our data. Variant chr1-17053998-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 480807.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-17053998-AG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.21del | p.Ser8ProfsTer2 | frameshift_variant | 1/8 | ENST00000375499.8 | |
SDHB | NM_001407361.1 | c.21del | p.Ser8ProfsTer2 | frameshift_variant | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.21del | p.Ser8ProfsTer2 | frameshift_variant | 1/8 | 1 | NM_003000.3 | P1 | |
SDHB | ENST00000466613.2 | n.33del | non_coding_transcript_exon_variant | 1/3 | 2 | ||||
SDHB | ENST00000485515.5 | n.9del | non_coding_transcript_exon_variant | 1/7 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 03, 2017 | The c.21delC pathogenic mutation, located in coding exon 1 of the SDHB gene, results from a deletion of one nucleotide at nucleotide position 21, causing a translational frameshift with a predicted alternate stop codon (p.S8Pfs*2). In a study of 598 unrelated probands diagnosed with head and neck paraganglioma, this alteration was detected in 1 individuals (Neumann HP et al. Cancer Res. 2009 Apr;69:3650-6). 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
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Prediction
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