rs1553179312
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_003000.3(SDHB):āc.72G>Cā(p.Gln24His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,459,928 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q24L) has been classified as Uncertain significance.
Frequency
Consequence
NM_003000.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.72G>C | p.Gln24His | missense_variant, splice_region_variant | 1/8 | ENST00000375499.8 | |
SDHB | NM_001407361.1 | c.72G>C | p.Gln24His | missense_variant, splice_region_variant | 1/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.72G>C | p.Gln24His | missense_variant, splice_region_variant | 1/8 | 1 | NM_003000.3 | P1 | |
SDHB | ENST00000466613.2 | n.84G>C | splice_region_variant, non_coding_transcript_exon_variant | 1/3 | 2 | ||||
SDHB | ENST00000485515.5 | n.60G>C | splice_region_variant, non_coding_transcript_exon_variant | 1/7 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459928Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726184
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 26, 2019 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SDHB-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with histidine at codon 24 of the SDHB protein (p.Gln24His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 1 of the SDHB coding sequence, which is part of the consensus splice site for this exon. - |
Hereditary pheochromocytoma-paraganglioma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 03, 2024 | This missense variant replaces glutamine with histidine at codon 24 of the SDHB protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with SDHB-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at