rs751000085

Positions:

• chr1-17028680-G-A
• chr1-17028680-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000375499.8(SDHB):​c.343C>T​(p.Arg115Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,824 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SDHB ENST00000375499.8 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 2.83

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]

ACMG classification

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 1-17028680-G-A is Pathogenic according to our data. Variant chr1-17028680-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 197210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17028680-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.343C>T	p.Arg115Ter	stop_gained	4/8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.343C>T	p.Arg115Ter	stop_gained	4/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.343C>T	p.Arg115Ter	stop_gained	4/8	1	NM_003000.3	ENSP00000364649	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251464 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135910

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: 0.00000137 AC: 2 AN: 1461824 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727222

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 04, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2023	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); This variant is associated with the following publications: (PMID: 24523625, 17200167, 25525159, 16317055, 25873086, 28503760, 21348866, 25683602, 28490599, 30352407, 31666924, 31447099, 32741965, 16405730, 35668420, 30050099, 32688340) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

Hereditary pheochromocytoma-paraganglioma Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 22, 2016	The p.Arg115X variant in SDHB has been reported in at least two individuals with hereditary paragangliomas and pheochromocytomas and segregated with disease in 1 affected relative (Bayley 2006, Benn 2006, Lefebvre 2006). It has also been id entified in 2/66740 European chromosomes by the Exome Aggregation Consortium (Ex AC, http://exac.broadinstitute.org; dbSNP rs751000085). This frequency is low en ough to be consistent with the frequency of hereditary paragangliomas and pheoch romocytomas in the general population. This nonsense variant is predicted to res ult in a premature termination codon at position 115, leading to a truncated or absent protein. Heterozygous loss-of-function variants in the SDHB gene are asso ciated with hereditary paragangliomas and pheochromocytomas. In summary, this va riant meets our criteria to be classified as pathogenic for hereditary paragangl iomas and pheochromocytomas in an autosomal dominant manner based on the predict ed impact to the protein and low frequency in controls. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 11, 2021	Variant summary: SDHB c.343C>T (p.Arg115X) 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. The variant allele was found at a frequency of 8e-06 in 251464 control chromosomes (gnomAD). c.343C>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (e.g. Bayley_2006, Benn_2006, Timmers_2007, Guan_2015, Richter_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 07, 2024	The c.343C>T (p.Arg115*) variant in the SDHB gene is located on the exon 4 and introduces a premature translation termination codon (p.Arg115*), resulting in an absent or disrupted protein product. The variant has been reported in multiple unrelated individuals with paragangliomas/pheochromocytoma (PMID: 30352407, 28490599, 31666924, 29386252, 32688340). Loss-of-function variants of SDHB are known to be pathogenic (PMID: 16258955, 19389109, 28490599). The variant is reported in ClinVar (ID: 197210). The variant is rare in general population according to gnomAD (2/251464). Therefore, the c.343C>T (p.Arg115*) variant of SDHB has been classified as pathogenic. -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change creates a premature translational stop signal (p.Arg115*) 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 (rs751000085, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with paraganglioma and/or pheochromocytoma (PMID: 16405730, 21348866, 24523625, 25047027, 28490599). ClinVar contains an entry for this variant (Variation ID: 197210). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

Paragangliomas 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Johns Hopkins Genomics, Johns Hopkins University

May 23, 2021

- -

Gastrointestinal stromal tumor Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 19, 2023

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2020

The p.R115* pathogenic mutation (also known as c.343C>T), located in coding exon 4 of the SDHB gene, results from a C to T substitution at nucleotide position 343. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has been reported in multiple patients with a personal history of paraganglioma and/or pheochromocytoma (Bayley JP et al. BMC Med. Genet., 2006 Jan;7:1; van Hulsteijn LT et al. Fam. Cancer, 2014 Dec;13:651-7; Martucci VL et al. Urol. Oncol., 2015 Apr;33:167.e13-20; Janssen I et al. Clin. Cancer Res., 2015 Sep;21:3888-95; Jochmanova I et al. J. Cancer Res. Clin. Oncol., 2017 Aug;143:1421-1435; Niemeijer ND et al. Eur. J. Endocrinol., 2017 Aug;177:115-125; Andrews KA et al. J. Med. Genet., 2018 06;55:384-394; Benn DE et al. J. Med. Genet., 2018 11;55:729-734; Huang Y et al. Endocr Connect, 2018 Dec;7:1217-1225; Richter S et al. Genet. Med., 2019 03;21:705-717). 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	0.61	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.79	D
MutationTaster	Benign	1.0	A
Vest4		0.97
GERP RS		4.2
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

Other links and lift over

dbSNP: rs751000085; hg19: chr1-17355175; COSMIC: COSV64965281; COSMIC: COSV64965281;