rs74315366

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_003000.3(SDHB):c.268C>T(p.Arg90Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000434 in 1,613,230 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

SDHB
NM_003000.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 3.85

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-17033078-G-A is Pathogenic according to our data. Variant chr1-17033078-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17033078-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3 linkuse as main transcript	c.268C>T	p.Arg90Ter	stop_gained	3/8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1 linkuse as main transcript	c.268C>T	p.Arg90Ter	stop_gained	3/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8 linkuse as main transcript	c.268C>T	p.Arg90Ter	stop_gained	3/8	1	NM_003000.3	ENSP00000364649	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251336

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460972

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726836

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Paragangliomas 4

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	UCLA Clinical Genomics Center, UCLA	Jan 21, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 08, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(R62*); This variant is associated with the following publications: (PMID: 26332594, 27573198, 17102068, 20061288, 25371406, 27171833, 16314641, 18419787, 25972245, 25525159, 22517557, 11404820, 28324028, 26230854, 21934479, 26464466, 23083876, 28374168, 19454582, 28973655, 15328326, 19576851, 12618761, 16317055, 24659481, 28748451, 30050099, 31666924, 31492822, 32804377, 32741965, 30787465, 33726816) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 18, 2021	This nonsense variant causes the premature termination of SDHB protein synthesis. In the published literature, the variant has been reported in individuals with paraganglioma, pheochromocytoma, gastrointestinal stromal tumor, and renal cell carcinoma (PMIDs: 28374168 (2017), 28324028 (2017), 23083876 (2012), 19454582 (2009), 18419787 (2008), and 11404820 (2001)). Therefore, the variant is classified as pathogenic. -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:3

Pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2019	The p.Arg90X variant in SDHB has previously been identified in at least 12 individuals with SDHB-associated tumors and segregated with disease in 9 affected family members from at least 5 families (Amar 2005, Zu 2011, Srirangalingam 2008, Benn 2006, Hensen 2012, Elston 2017, Gill 2011, Lee 2014, Crona 2014, Burnichon 2009, Benn 2003). It has also been identified in 2/113664 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar (Variation ID 12778). This nonsense variant leads to a premature termination codon at position 90, which is predicted to lead to a truncated or absent protein. Functional studies support an impact on protein function (Kim 2015, Elston 2017). Heterozygous loss of function of the SDHB gene is an established disease mechanism in patients with hereditary paraganglioma and pheochromocytoma. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary paraganglioma and pheochromocytoma. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate, PS3_Supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 17, 2022	Variant summary: SDHB c.268C>T (p.Arg90X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251336 control chromosomes (gnomAD). c.268C>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (e.g. Astuti_2001, Benn_2006, Andrews_2018). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant has no protein activity (Kim_2015). Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Von Hippel-Lindau syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)

May 10, 2023

- -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1861848:Paragangliomas 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 04, 2023

This sequence change creates a premature translational stop signal (p.Arg90*) in the SDHB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). This variant is present in population databases (rs74315366, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with pheochromocytoma, paraganglioma and renal cell carcinoma (PMID: 11404820, 12618761, 16314641, 16317055, 18419787, 19454582, 21348866, 21934479, 23083876, 24466223, 25326637). This variant is also known as R91X. ClinVar contains an entry for this variant (Variation ID: 12778). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2024

The p.R90* pathogenic mutation (also known as c.268C>T), located in coding exon 3 of the SDHB gene, results from a C to T substitution at nucleotide position 268. This changes the amino acid from an arginine to a stop codon within coding exon 3. This pathogenic mutation has been reported in multiple unrelated families exhibiting pheochromocytomas and/or paragangliomas (Astuti D et al. Am J Hum Genet. 2001 Jul;69(1):49-54; Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91:827-36; Ricketts CJ et al. J Urol. 2012 Dec;188(6):2063-71; Crona J et al. PLoS One. 2014 Jan;9(1):e86756; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143(8):1421-1435; Albattal S et al. Oncotarget. 2019 Oct 15;10(57):5919-5931). This mutation has also been identified in a woman with a renal tumor and family history of paragangliomas, where the renal tumor demonstrated negative SDHB staining by immunohistochemistry (Gill AJ et al. Am. J. Surg. Pathol. 2011 Oct;35:1578-85). It was recently seen in a patient with a duodenal GIST who also had a family history of paragangliomas. IHC analysis of the GIST showed negative SDHB staining, and the tumor was positive for the p.R90* mutation (Elston MS et al. J. Clin. Endocrinol. Metab. 2017 May;102(5):1447-1450). In vitro data showed complete loss of SDHB expression in cytosolic and mitochondrial compartments as well as no measurable SDH activity in cells transfected with this truncating mutation (Kim E et al. Endocr. Relat. Cancer 2015 Jun;22:387-97). Of note, this mutation is referred to as p.R91X in the Astuti (2001) paper. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

Vest4

0.98

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

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