1-17028736-C-T
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_003000.3(SDHB):c.287G>A(p.Gly96Asp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G96S) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003000.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHB | NM_003000.3 | c.287G>A | p.Gly96Asp | missense_variant, splice_region_variant | 4/8 | ENST00000375499.8 | |
SDHB | NM_001407361.1 | c.287G>A | p.Gly96Asp | missense_variant, splice_region_variant | 4/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHB | ENST00000375499.8 | c.287G>A | p.Gly96Asp | missense_variant, splice_region_variant | 4/8 | 1 | NM_003000.3 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251204Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135794
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461622Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727116
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74328
ClinVar
Submissions by phenotype
Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 14, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 96 of the SDHB protein (p.Gly96Asp). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 428916). This missense change has been observed in individuals with paraganglioma, pheochromocytoma or renal cell carcinoma (PMID: 16317055, 17538171, 19075037, 28891197; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs778952116, gnomAD 0.02%). - |
Paragangliomas 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2023 | The p.G96D variant (also known as c.287G>A) is located in coding exon 4 of the SDHB gene. The glycine at codon 96 is replaced by aspartic acid, an amino acid with similar properties. This variant has been reported in multiple individuals diagnosed with paragangliomas and/or pheochromocytomas (Benn DE et al. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36; Timmers HJ et al. J Clin Endocrinol Metab. 2008 Dec;93(12):4826-32; Ghayee HK et al. Endocr. Relat. Cancer, 2009 Mar;16:291-9; Jochmanova I et al. J. Cancer Res. Clin. Oncol., 2017 Aug;143:1421-1435; Samuel N et al. J Surg Oncol, 2018 Feb;117:160-162; Guha A et al. Biomedicines, 2021 May;9:; Gordon DM et al. Endocr Connect, 2022 Jan;11:; 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. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Hereditary pheochromocytoma-paraganglioma Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Section on Medical Neuroendocrinolgy, National Institutes of Health | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at