1-17028727-C-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_003000.3(SDHB):​c.296G>A​(p.Gly99Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. G99S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

SDHB
NM_003000.3 missense

Scores

16
2
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.23

Publications

6 publications found
Variant links:
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]
SDHB Gene-Disease associations (from GenCC):
  • Carney-Stratakis syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
  • gastrointestinal stromal tumor
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
  • hereditary pheochromocytoma-paraganglioma
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • pheochromocytoma
    Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
  • pheochromocytoma/paraganglioma syndrome 4
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • mitochondrial disease
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • renal cell carcinoma
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • mitochondrial complex 2 deficiency, nuclear type 4
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • Cowden disease
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • mitochondrial complex II deficiency
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_003000.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 1-17028727-C-T is Pathogenic according to our data. Variant chr1-17028727-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 239428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SDHBNM_003000.3 linkc.296G>A p.Gly99Asp missense_variant Exon 4 of 8 ENST00000375499.8 NP_002991.2 P21912
SDHBNM_001407361.1 linkc.296G>A p.Gly99Asp missense_variant Exon 4 of 8 NP_001394290.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SDHBENST00000375499.8 linkc.296G>A p.Gly99Asp missense_variant Exon 4 of 8 1 NM_003000.3 ENSP00000364649.3 P21912

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Jul 25, 2022
GeneDx
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with paraganglioma and/or pheochromocytoma (Benn et al., 2006; Andrews et al., 2018; Bayley et al., 2020); This variant is associated with the following publications: (PMID: 15989954, 16317055, 29386252, 33162331, 19802898, 25972245, 19215943, 31492822, 29315604) -

Pheochromocytoma/paraganglioma syndrome 4 Pathogenic:1
Nov 07, 2024
Molecular Pathology, Peter Maccallum Cancer Centre
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 Pathogenic:1
Dec 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 99 of the SDHB protein (p.Gly99Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paraganglioma and/or pheochromocytoma (PMID: 16317055, 31492822; internal data). ClinVar contains an entry for this variant (Variation ID: 239428). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1
Jun 17, 2024
Ambry Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.G99D variant (also known as c.296G>A), located in coding exon 4 of the SDHB gene, results from a G to A substitution at nucleotide position 296. The glycine at codon 99 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been identified in multiple individuals with personal and/or family history of paraganglioma and/or pheochromocytoma (Benn DE et al. J Clin Endocrinol Metab, 2006 Mar;91:827-36; Andrews KA et al. J Med Genet, 2018 06;55:384-394; Bayley JP et al. J Med Genet, 2020 02;57:96-103). 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 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.94
D;.;D
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Pathogenic
0.99
D;D;D
M_CAP
Pathogenic
0.49
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.93
D
MutationAssessor
Pathogenic
4.6
H;.;.
PhyloP100
7.2
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-6.4
D;.;.
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;.;.
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.98
MutPred
0.96
Loss of sheet (P = 0.1158);.;.;
MVP
0.98
MPC
0.79
ClinPred
1.0
D
GERP RS
6.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.92
Mutation Taster
=2/98
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs878854576; hg19: chr1-17355222; API