rs1060503757

Positions:

• chr1-17024023-TG-T

Variant summary

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

The NM_003000.3(SDHB):​c.591del​(p.Ser198AlafsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P197P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHB NM_003000.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -0.601

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 1-17024023-TG-T is Pathogenic according to our data. Variant chr1-17024023-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 412462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17024023-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.591del	p.Ser198AlafsTer22	frameshift_variant	6/8	ENST00000375499.8
SDHB	NM_001407361.1	c.537del	p.Ser180AlafsTer22	frameshift_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.591del	p.Ser198AlafsTer22	frameshift_variant	6/8	1	NM_003000.3	P1
SDHB	ENST00000491274.6	c.549del	p.Ser184AlafsTer22	frameshift_variant	6/8	5
SDHB	ENST00000463045.3	c.420del	p.Ser141AlafsTer22	frameshift_variant	6/8	3
SDHB	ENST00000485515.5	n.525del		non_coding_transcript_exon_variant	6/7	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 14, 2016	The c.591delC pathogenic mutation, located in coding exon 6 of the SDHB gene, results from a deletion of one nucleotide at position 591 causing a translational frameshift with a predicted alternate stop codon. This pathogenic alteration has been reported in several unrelated individuals diagnosed with paraganglioma or pheochromocytoma (Amar L et al. .J Clin. Oncol. 2005 Dec 1;23(34):8812-8; Fakhry N et al. Eur. Arch. Otorhinolaryngol. 2008 May;265(5):557-63; 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 or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 05, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 412462). This premature translational stop signal has been observed in individuals with paraganglioma-pheochromocytoma syndrome (PMID: 16314641, 16317055, 19454582, 22517554, 23072324). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser198Alafs*22) 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). -

Paragangliomas 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2001

- -

Gastrointestinal stromal tumor Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

SDHB-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Jan 05, 2022

The c.591del;p.(Ser198Alafs*22) is a null frameshift variant (NMD) in the SDHB gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 412462; PMID: 22517554; 19454582; 23072324; 16314641; 16317055) - PS4. This variant is not present in population databases (rs1060503757, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is 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: rs1060503757; hg19: chr1-17350518;