1-17027735-TAGGGACTAATGACC-T

Position:

• chr1-17027735-TAGGGACTAATGACC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003000.3(SDHB):​c.540_540+13delGGTCATTAGTCCCT​(p.Asp181fs) variant causes a frameshift, splice donor, splice region, intron change. 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. L180L) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHB NM_003000.3 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.98

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]

SDHB (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 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 1-17027735-TAGGGACTAATGACC-T is Pathogenic according to our data. Variant chr1-17027735-TAGGGACTAATGACC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 468236.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.540_540+13delGGTCATTAGTCCCT	p.Asp181fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	5/8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.486_486+13delGGTCATTAGTCCCT	p.Asp163fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	5/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.540_540+13delGGTCATTAGTCCCT	p.Asp181fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	5/8	1	NM_003000.3	ENSP00000364649.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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

Jul 09, 2020

This sequence change affects a donor splice site in intron 5 of the SDHB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with paraganglioma (Invitae). ClinVar contains an entry for this variant (Variation ID: 468236). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHB are known to be pathogenic (PMID: 19802898, 19454582). 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. -

Paragangliomas 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2017

This sequence change affects a donor splice site in intron 5 of the SDHB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SDHB-related disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHB are known to be pathogenic (PMID: 19802898, 19454582). 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. -

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: rs1553177666; hg19: chr1-17354230;