rs1060503752

Variant names:

• chr1-17023993-CCA-C
• rs1060503752
• NM_003000.3:c.620_621delTG

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.620_621delTG​(p.Leu207ArgfsTer14) 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L207L) 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:2
• Conservation: PhyloP100: 8.31

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 1-17023993-CCA-C is Pathogenic according to our data. Variant chr1-17023993-CCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 412454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17023993-CCA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHB	NM_003000.3	c.620_621delTG	p.Leu207ArgfsTer14	frameshift_variant	Exon 6 of 8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.566_567delTG	p.Leu189ArgfsTer14	frameshift_variant	Exon 6 of 8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.620_621delTG	p.Leu207ArgfsTer14	frameshift_variant	Exon 6 of 8	1	NM_003000.3	ENSP00000364649.3
SDHB	ENST00000491274.6	c.578_579delTG	p.Leu193ArgfsTer14	frameshift_variant	Exon 6 of 8	5		ENSP00000480482.2
SDHB	ENST00000463045.3	c.449_450delTG	p.Leu150ArgfsTer14	frameshift_variant	Exon 6 of 8	3		ENSP00000481376.2
SDHB	ENST00000485515.5	n.554_555delTG		non_coding_transcript_exon_variant	Exon 6 of 7	5		ENSP00000519322.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma;C1861848:Paragangliomas 4 Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PM2_Supporting+PS4_Moderate -

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

Mar 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 412454). This variant is also known as 754–755 del TG. This premature translational stop signal has been observed in individual(s) with pheochromocytomas (PCC) and/or paragangliomas (PGL) (PMID: 14500403, 16314641, 19454582, 25405498, 30877234). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu207Argfs*14) 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). -

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: rs1060503752; hg19: chr1-17350488;