rs786203010

chr1-17044872-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_003000.3(SDHB):c.88del(p.Gln30ArgfsTer47) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000753 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q30Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SDHB NM_003000.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.12

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 16 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 281 pathogenic variants in the truncated region.
• PP5: Variant 1-17044872-TG-T is Pathogenic according to our data. Variant chr1-17044872-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 186518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17044872-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.88del	p.Gln30ArgfsTer47	frameshift_variant	2/8	ENST00000375499.8
SDHB	NM_001407361.1	c.88del	p.Gln30ArgfsTer47	frameshift_variant	2/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.88del	p.Gln30ArgfsTer47	frameshift_variant	2/8	1	NM_003000.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251110 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135744

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461706 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727174

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

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

Invitae

Jun 17, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 186518). This premature translational stop signal has been observed in individual(s) with clinical features of hereditary paraganglioma-pheochromocytoma (PGL-PCC) syndrome (PMID: 12618761, 19596260, 24395865). This variant is present in population databases (rs747198089, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln30Argfs*47) 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). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2019

The c.88delC pathogenic mutation, located in coding exon 2 of the SDHB gene, results from a deletion of one nucleotide at position 88, causing a translational frameshift with a predicted alternate stop codon. This alteration has been identified in multiple individuals in the literature who had a personal and/or family history of PGL/PCC (Benn DE et al. J. Med. Genet. 2018 Nov;55(11):729-734; Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394), including a 12-year-old male diagnosed with an abdominal PGL/PCC (Benn, DE et al. Oncogene. 2003 Mar 6;22(9):1358-64), and a 13-year-old male diagnosed with 3 simultaneous extra-adrenal PGLs whose tumor showed loss of heterozygosity (LOH) at the SDHB locus (Prasad P et al. Cancer Genet Cytogenet. 2009;192(2):82-85). This mutation has also been reported in an individual diagnosed with bilateral renal carcinoma at age 27. His unaffected mother was also a carrier and there was no known family history of PGL/PCC (Paik, JY et al. J Clin Oncol. 2014 Feb 20;32(6):e10-3). 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 when compared to wildtype, indicating nonsense-mediated mRNA decay or protein degradation as a mechanism for absent enzymatic activity (Kim E, Endocr. Relat. Cancer 2015 Jun; 22(3):387-97). In addition to the clinical and functional data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Section on Medical Neuroendocrinolgy, National Institutes of Health

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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: rs747198089; hg19: chr1-17371367;