rs876660642

Positions:

• chr1-17022659-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_003000.3(SDHB):​c.713del​(p.Phe238SerfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SDHB NM_003000.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.67

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-17022659-GA-G is Pathogenic according to our data. Variant chr1-17022659-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 233795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17022659-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.713del	p.Phe238SerfsTer10	frameshift_variant	7/8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.659del	p.Phe220SerfsTer10	frameshift_variant	7/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.713del	p.Phe238SerfsTer10	frameshift_variant	7/8	1	NM_003000.3	ENSP00000364649	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251466 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135912

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461806 Hom.: 0 Cov.: 31 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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 12, 2023

This variant is also known as c.713delT (p.Phe238fs). This premature translational stop signal has been observed in individual(s) with paraganglioma-pheochromocytoma syndromes (PMID: 16317055, 19454582, 22517554, 28490599). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Phe238Serfs*10) in the SDHB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acid(s) of the SDHB protein. ClinVar contains an entry for this variant (Variation ID: 233795). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SDHB protein in which other variant(s) (p.Leu240Serfs*16) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. -

Gastrointestinal stromal tumor Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Apr 19, 2023

_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2019

The c.713delT pathogenic mutation, located in coding exon 7 of the SDHB gene, results from a deletion of one nucleotide at nucleotide position 713, causing a translational frameshift with a predicted alternate stop codon (p.F238Sfs*10). This mutation has been identified in several individuals with paraganglioma (PGL) and/or pheochromocytoma (PCC) (Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91(3):827-36; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94(8):2817-27; Rijken JA et al. Clin. Genet. 2018 Jan;93:60-66). In addition, loss of heterozygosity at the SDHB locus was established in the tumor of a germline carrier of this mutation (Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94(8):2817-27). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 08, 2024

This variant deletes 1 nucleotide in exon 7 of the SDHB gene, creating a frameshift and premature translation stop signal in exon 7. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. This variant has been reported in individuals affected with hereditary paraganglioma-pheochromocytoma syndrome (PMID: 16317055, 19454582, 22517554, 28490599). Downstream truncations are known to be disease-causing (ClinVar variation ID: 12782, 412481, 201607, 421424). This variant has been identified in 1/251466 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SDHB function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs876660642; hg19: chr1-17349154;