1-17033077-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_003000.3(SDHB):c.269G>A(p.Arg90Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,613,296 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. R90L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

SDHB
NM_003000.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:7

Conservation

PhyloP100: 6.92

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_003000.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-17033077-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1493254.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.984

PP5

Variant 1-17033077-C-T is Pathogenic according to our data. Variant chr1-17033077-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201609.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=5}. Variant chr1-17033077-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHB	NM_003000.3 link	c.269G>A	p.Arg90Gln	missense_variant	Exon 3 of 8	ENST00000375499.8	NP_002991.2	P21912
SDHB	NM_001407361.1 link	c.269G>A	p.Arg90Gln	missense_variant	Exon 3 of 8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8 link	c.269G>A	p.Arg90Gln	missense_variant	Exon 3 of 8	1	NM_003000.3	ENSP00000364649.3		P21912

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251332

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1460960

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726850

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152336

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000288

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SDHB: PM5, PM2:Supporting, PS3:Supporting, PS4:Supporting -

Sep 17, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function Published functional studies in yeast demonstrate reduced SDH activity (Panizza 2013) Observed in individuals with SDHB-related tumors (Castellano 2006, Neumann 2009, Hermsen 2010, Curras-Freixes 2015, Bernardo-Castineira 2019) -

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:1Uncertain:1

Jul 29, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with glutamine at codon 90 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional complementation studies in yeast have reported mildly impaired SDHB protein function (PMID: 23175444). This variant has been reported in individuals affected with hereditary paranganglioma-pheochromocytoma syndrome in the literature (PMID: 17102082, 19351833, 20208144, 26102504 , 26269449, 30549360, 31216007), but has also been reported in unaffected individuals (ClinVar Variation ID: VCV000201609, SCV000581189.5). This variant has been identified in 3/282738 chromosomes 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. -

Oct 28, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SDHB c.269G>A (p.Arg90Gln) results in a conservative amino acid change located in the 2Fe-2S ferredoxin-type iron-sulfur binding domain (IPR001041) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251332 control chromosomes. c.269G>A has been reported in the literature in comprehensively genotyped cohorts of individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome and in at-least one individual with bilateral breast cancer example, Neumann_2009, Castellano_2006, Hermsen_2010, Curras-Freixes_2015, Bernardo-Castineira_2019, Moradian_2021). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect as it has been shown to reduce but not entirely abolish SDHB enzymatic activity in a yeast experimental system (Panizza_2013). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=4; likely pathogenic, n=1). Some submitters cite overlapping but not identical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4

Pathogenic:1

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 90 of the SDHB protein (p.Arg90Gln). This variant is present in population databases (rs570278423, gnomAD 0.008%). This missense change has been observed in individuals with breast cancer and/or paraganglioma-pheochromocytoma syndromes (PMID: 17102082, 19351833, 20208144, 21520333, 26269449, 33558524, 34906457). ClinVar contains an entry for this variant (Variation ID: 201609). 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%. Experimental studies have shown that this missense change affects SDHB function (PMID: 23175444). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

bilateral breast cancer

Uncertain:1

Jul 22, 2020

Center of Medical Genetics and Primary Health Care

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

ACMG Guidelines 2015 criteria This variant is in exon 3 of the SDHB gene in the Fer2_3 domain (F42-147Y aa); it is involved in electron transfer activity, iron-sulfur cluster binding. This missense change has been shown to reduce but not entirely abolish SDHB enzymatic activity (PMID: 23175444) (PS3 Pathogenic Very Strong). This variant has been reported as pathogenic in paraganglioma (Panizzaet al., 2013). This variant is in a hotspot of 10 pathogenic missense, nonsense, and frameshift variants (source ClinVar) (PM1 Pathogenic Moderate). There is a known pathogenic null (terminating) variant (i.e., c.268C>T (p.Arg90Ter) at the same amino acid residue which also suggests that this region is a mutational hotspot (PS1 Pathogenic Strong). The allele count in GnomAD exomes and GnomAD genomes are 2 and 1, respectively, which are less the threshold 5 for dominant gene SDHB (PM2 Pathogenic Moderate). 11 pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT versus no benign predictions support its deleterious effect (PP3 Pathogenic Supporting). This variant is reported in ClinVar as a likely pathogenic variant or a VUS. In this study this variant was found in a 46-year-old female with bilateral breast cancer and no reported family history of cancer. Based on the evidence provided above, we classified this variant as a Variant of Unknown Significance. -

Gastrointestinal stromal tumor

Uncertain:1

Feb 15, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Oct 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R90Q variant (also known as c.269G>A), located in coding exon 3 of the SDHB gene, results from a G to A substitution at nucleotide position 269. The arginine at codon 90 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in several individuals with a paraganglioma (Castellano M et al. Ann. N. Y. Acad. Sci., 2006 Aug;1073:156-65; Neumann HP et al. Cancer Res., 2009 Apr;69:3650-6; Hermsen MA et al. Cell. Oncol., 2010 Jan;32:275-83; Currás-Freixes M et al. J Med Genet, 2015 Oct;52:647-56). At our laboratory, the variant has been detected in over 20 individuals; none of them reported to have a paraganglioma (Ambry internal data). This variant was also detected in an individual a gastrointestinal stromal tumor, which retained SDHB expression on immunostaining (Klinke OK et al. PLoS One, 2015 Jun;10:e0130149). One functional study demonstrated that the yeast equivalent of this variant moderately impairs succinate dehydrogenase function (Panizza E et al. Hum Mol Genet, 2013 Feb;22:804-15). 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 available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.94

D;.;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

4.6

H;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.6

D;.;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.98

MutPred

0.97

Gain of sheet (P = 0.0344);.;.;

MVP

0.96

MPC

0.74

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.28

Position offset: -17

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over