rs786201316
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PS1PM2PP5_Very_Strong
The NM_003000.3(SDHB):c.311delAinsGG(p.Asn104ArgfsTer15) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N104K) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_003000.3 frameshift, missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.311delAinsGG | p.Asn104ArgfsTer15 | frameshift_variant, missense_variant | Exon 4 of 8 | ENST00000375499.8 | NP_002991.2 | |
SDHB | NM_001407361.1 | c.311delAinsGG | p.Asn104ArgfsTer15 | frameshift_variant, missense_variant | Exon 4 of 8 | NP_001394290.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Frameshift 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 (gnomAD); Published functional studies demonstrate a damaging effect: impaired enzymatic activity (PMID: 25972245); This variant is associated with the following publications: (PMID: 36786389, 16317055, 19215943, 26273102, 31492822, 30694796, 30201732, 29386252, 25972245) -
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Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1
This sequence change creates a premature translational stop signal (p.Asn104Argfs*15) 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 and paraganglioma (PMID: 16317055, 25972245, 31492822). This variant is also known as c.311delAinsGG. For these reasons, this variant has been classified as Pathogenic. -
Paragangliomas 4 Pathogenic:1
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.311delAinsGG pathogenic mutation, located in coding exon 4 of the SDHB gene, results from the deletion of one nucleotide and insertion of two nucleotides at position 311, causing a translational frameshift with a predicted alternate stop codon (p.N104Rfs*15). This mutation has been described in a patient with a history of pheochromocytoma and head and neck paraganglioma (Benn DE et al. J Clin Endocrinol Metab. 2006;91(3):827-36). It was also identified in two related patients who were diagnosed with paraganglimoas in adolescence (Tufton N et al. Endocr Connect. 2019 Mar;8(3):162-172). 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
The SDHB c.311delinsGG variant is predicted to result in a frameshift and premature protein termination (p.Asn104Argfs*15). This variant has been reported in an individuals with pheochromocytoma and/or paraganglioma (Table 1, Benn et al. 2006. PubMed ID: 16317055; Table 1, Tufton et al. 2019. PubMed ID: 30694796). In vitro experimental studies indicate this variant impacts protein function (Figure 2, Kim et al. 2015. PubMed ID: 25972245). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/184177/). Frameshift variants in SDHB are expected to be pathogenic. This variant is interpreted as pathogenic. -
Hereditary pheochromocytoma-paraganglioma Pathogenic:1
This variant is predicted to result in loss of protein function through nonsense-mediated decay or protein truncation. Loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. This variant has been reported in multiple individuals with phaeochromocytoma and paraganglioma (PMID: 36786389, 30201732, 29386252, 26273102, 25972245, 16317055). This variant is present in 1/251424 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at