rs1553176976

Positions:

• chr1-17018936-A-ATAGC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_003000.3(SDHB):​c.787_788insGCTA​(p.Ile263SerfsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I263I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHB NM_003000.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.22

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0664 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-17018936-A-ATAGC is Pathogenic according to our data. Variant chr1-17018936-A-ATAGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 421424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.787_788insGCTA	p.Ile263SerfsTer13	frameshift_variant	8/8	ENST00000375499.8
SDHB	NM_001407361.1	c.733_734insGCTA	p.Ile245SerfsTer13	frameshift_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.787_788insGCTA	p.Ile263SerfsTer13	frameshift_variant	8/8	1	NM_003000.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 22, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 421424). This premature translational stop signal has been observed in individuals with paraganglioma or pheochromocytoma (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile263Serfs*13) in the SDHB gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the SDHB protein. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 27, 2017

This duplication of four nucleotides in SDHB is denoted c.784_787dupGCTA at the cDNA level and p.Ile263SerfsX13 (I263SfsX13) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is GAAA[dupGCTA]TTGC. The duplication causes a frameshift which changes an Isoleucine to a Serine at codon 263, and creates a premature stop codon at position 13 of the new reading frame. Even though nonsense-mediated decay is not expected to occur due to the position of the variant, it is significant since the last 18 amino acids are no longer translated correctly and is predicted to cause loss of normal protein function through protein truncation. Although this variant has not, to our knowledge, been reported in the literature, the disrupted region includes several residues that are conserved across species, and other nonsense or frameshift variants causing a similar impact have been reported in individuals with paraganglioma or pheochromocytoma (Neumann 2009, Rattenberry 2013, Pai 2015). Based on currently available information, we consider SDHB c.784_787dupGCTA to be a likely pathogenic variant. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2015

The c.784_787dupGCTA variant, located in coding exon 8 of the SDHB gene, results from a duplication of GCTA at nucleotide position 784 through 787, causing a translational frameshift with a predicted alternate stop codon. Per ACMG guidelines this variant could be interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294); however, this duplication and subsequent frameshift occur at the 3' terminus of SDHB and impact only the last 18 amino acids of the protein. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553176976; hg19: chr1-17345431;