rs74315369

chr1-17044882-G-Achr1-17044882-G-Cchr1-17044882-G-T

Variant summary

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

The NM_003000.3(SDHB):c.79C>T(p.Arg27Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000186 in 1,613,380 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SDHB
NM_003000.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 5.92

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 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 284 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-17044882-G-A is Pathogenic according to our data. Variant chr1-17044882-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17044882-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3 linkuse as main transcript	c.79C>T	p.Arg27Ter	stop_gained	2/8	ENST00000375499.8
SDHB	NM_001407361.1 linkuse as main transcript	c.79C>T	p.Arg27Ter	stop_gained	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8 linkuse as main transcript	c.79C>T	p.Arg27Ter	stop_gained	2/8	1	NM_003000.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250516

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135486

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461382

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727022

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:

0.0000116

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151998

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Paragangliomas 4

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Feb 06, 2018	This c.79C>T (p.R27) variant is predicted to result in a premature stop codon and has been reported in individuals with pheochromocytoma, paraganglioma and early-onset renal cell cancer (PMID: 12000816, 25215250, 18382370, 14685938, 14685938). In addition, in vitro studies have shown that the c.79C>T (p.R27) variant alters SDHB expression and function. Therefore we classify this variant as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 09, 2002	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 27, 2021	ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderate -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:2

Pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 19, 2023	Variant summary: SDHB c.79C>T (p.Arg27X) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250516 control chromosomes. c.79C>T has been reported in the literature in related individuals affected with Cardiac Paraganglioma, Renal cancer and Lung cancer (Example: Vanharanta_2004). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 14685938). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2023

This variant is also known as C213T. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 12783). This premature translational stop signal has been observed in individual(s) with pheochromocytoma (PMID: 12000816, 12362046, 14685938, 18382370, 19415531, 25215250). This variant is present in population databases (rs74315369, gnomAD 0.005%). This sequence change creates a premature translational stop signal (p.Arg27*) 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). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 08, 2022

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; Observed in individuals with pheochromocytoma and/or paraganglioma as well as in an individual with early-onset renal cell carcinoma (Cascn 2002, Neumann 2004, Vanharanta 2004, Klein 2008, Naito 2009, Merlo 2013, Graham 2014, Jochmanova 2017); Published functional studies demonstrate a damaging effect: absent SDHB protein production, absent SHD enzymatic activity, and abolished association with SDHA (Kim 2015); Not observed at significant frequency in large population cohorts (gnomAD); Also known as SDHB 213C>T; This variant is associated with the following publications: (PMID: 31579262, 12000816, 19184535, 26916530, 12362046, 14685938, 15476441, 15328326, 18728280, 17102084, 12213855, 22517557, 25215250, 23902947, 19343621, 19415531, 18382370, 28374168, 30694796, 31447099, 31492822, 30787465, 31666924, 34439168, 29625052, 25972245) -

Gastrointestinal stromal tumor

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 13, 2023

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2023

The p.R27* pathogenic mutation (also known as c.79C>T), located in coding exon 2 of the SDHB gene, results from a C to T substitution at nucleotide position 79. This changes the amino acid from an arginine to a stop codon within coding exon 2. The predicted stop codon occurs within the first 150 nucleotides of SDHB gene. This alteration may escape nonsense-mediated mRNAdecay and/or be rescued by re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653), and it impacts the first 57 amino acids of the protein. However, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). This mutation has previously been reported in multiple cases of both sporadic and familial PGL-PCC as well as renal cell carcinoma (Cascón A et al. J. Med. Genet., 2002 Oct;39:E64; Vanharanta S et al. Am. J. Hum. Genet., 2004 Jan;74:153-9; Neumann HP et al. JAMA, 2004 Aug;292:943-51; Naito M et al. Endocrine, 2009 Aug;36:10-5; Graham D et al. Case Rep Genet, 2014 Aug;2014:273423; Casey RT et al. J. Clin. Endocrinol. Metab., 2017 11;102:4013-4022; Fife K et al. BMJ Case Rep, 2017 Aug;2017; Benn DE et al. J. Med. Genet., 2018 11;55:729-734; Albattal S et al. Oncotarget, 2019 Oct;10:5919-5931). Functional studies of this alteration have demonstrated the absence of SDH enzymatic activity as well as the absence of SDHB protein in cell-based assays, indicating nonsense-mediated mRNA decay or protein degradation as a mechanism for absent enzymatic activity (Kim E et al. Endocr. Relat. Cancer, 2015 Jun;22:387-97). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.60

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.96

MutationTaster

Benign

1.0

Vest4

0.91

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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

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