chr1-17022612-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_003000.3(SDHB):c.761C>T(p.Pro254Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P254A) has been classified as Uncertain significance.
Frequency
Consequence
NM_003000.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.761C>T | p.Pro254Leu | missense_variant | 7/8 | ENST00000375499.8 | |
SDHB | NM_001407361.1 | c.707C>T | p.Pro236Leu | missense_variant | 7/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.761C>T | p.Pro254Leu | missense_variant | 7/8 | 1 | NM_003000.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461608Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727124
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 17, 2022 | The p.P254L variant (also known as c.761C>T), located in coding exon 7 of the SDHB gene, results from a C to T substitution at nucleotide position 761. The proline at codon 254 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in multiple individuals with paragangliomas (Lima J et al. J Clin Endocrinol Metab, 2007 Dec;92:4853-64; Neumann HP et al. Cancer Res, 2009 Apr;69:3650-6; Burnichon N et al. J Clin Endocrinol Metab, 2009 Aug;94:2817-27; Hermsen MA et al. Cell Oncol, 2010 Jan;32:275-83; Rijken JA et al. BJS Open, 2018 Apr;2:62-69; Bernardo-Castiñeira C et al. Head Neck, 2019 01;41:79-91; Donato S et al. Endocrine, 2019 08;65:408-415). Based on internal structural analysis, p.P254L is considered deleterious (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 254 of the SDHB protein (p.Pro254Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paraganglioma (PGL) and/or paraganglioma-pheochromocytoma syndromes (PMID: 17848412, 19351833, 19454582, 20208144, 29951630, 34750850, 34906457). ClinVar contains an entry for this variant (Variation ID: 412459). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. This variant disrupts the p.Pro254 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been observed in individuals with SDHB-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at