NM_003000.3:c.*159_*184delAGAACCTGTTCCTTTACTTGCCGCAGinsGAACCTGTTCCTTTACTTGCCCCAA

Variant names:

• chr1-17018697-CTGCGGCAAGTAAAGGAACAGGTTCT-TTGGGGCAAGTAAAGGAACAGGTTC
• rs727503414
• NM_003000.3:c.*159_*184delAGAACCTGTTCCTTTACTTGCCGCAGinsGAACCTGTTCCTTTACTTGCCCCAA

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003000.3(SDHB):​c.*159_*184delAGAACCTGTTCCTTTACTTGCCGCAGinsGAACCTGTTCCTTTACTTGCCCCAA variant causes a splice region 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHB NM_003000.3 splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHB	NM_003000.3	c.*159_*184delAGAACCTGTTCCTTTACTTGCCGCAGinsGAACCTGTTCCTTTACTTGCCCCAA		splice_region_variant	Exon 8 of 8	ENST00000375499.8	NP_002991.2
SDHB	NM_003000.3	c.*159_*184delAGAACCTGTTCCTTTACTTGCCGCAGinsGAACCTGTTCCTTTACTTGCCCCAA		3_prime_UTR_variant	Exon 8 of 8	ENST00000375499.8	NP_002991.2
SDHB	NM_003000.3	c.*159_*184delAGAACCTGTTCCTTTACTTGCCGCAGinsGAACCTGTTCCTTTACTTGCCCCAA		non_coding_transcript_variant		ENST00000375499.8	NP_002991.2
SDHB	NM_003000.3	c.*159_*184delAGAACCTGTTCCTTTACTTGCCGCAGinsGAACCTGTTCCTTTACTTGCCCCAA		downstream_gene_variant		ENST00000375499.8	NP_002991.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.*159_*184delAGAACCTGTTCCTTTACTTGCCGCAGinsGAACCTGTTCCTTTACTTGCCCCAA		splice_region_variant	Exon 8 of 8	1	NM_003000.3	ENSP00000364649.3
SDHB	ENST00000375499	c.*159_*184delAGAACCTGTTCCTTTACTTGCCGCAGinsGAACCTGTTCCTTTACTTGCCCCAA		3_prime_UTR_variant	Exon 8 of 8	1	NM_003000.3	ENSP00000364649.3
SDHB	ENST00000375499.8	c.*159_*184delAGAACCTGTTCCTTTACTTGCCGCAGinsGAACCTGTTCCTTTACTTGCCCCAA		non_coding_transcript_variant		1	NM_003000.3	ENSP00000364649.3
SDHB	ENST00000375499.8	c.*159_*184delAGAACCTGTTCCTTTACTTGCCGCAGinsGAACCTGTTCCTTTACTTGCCCCAA		downstream_gene_variant		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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Feb 27, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.*159_*184delins25 variant in SDHB has been identified in >10 individuals with pheochromocytomas, paragangliomas, or GIST, 7 of whom carried a second variant sufficient to explain disease (Hernandez 2015 PMID 25800244, LMM data). Data from large population studies is insufficient to assess the frequency of this variant. This variant is located in the 3' untranslated region (3' UTR) and while this region may contain important regulatory sequences, no pathogenic variants in the SDHB gene have been reported in this region. In summary, while the clinical significance of the c.*159_*184delins25 variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP criteria applied: BP5 -

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: rs727503414; hg19: chr1-17345192;