1-17018883-A-C

Variant names:

• chr1-17018883-A-C
• rs1316826258
• NM_003000.3:c.841T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_003000.3(SDHB):​c.841T>G​(p.Ter281Gluext*?) variant causes a stop lost change. The variant allele was found at a frequency of 0.000000687 in 1,454,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SDHB NM_003000.3 stop_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.80
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Carney-Stratakis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• pheochromocytoma/paraganglioma syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• mitochondrial complex 2 deficiency, nuclear type 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_003000.3 Downstream stopcodon found after 65 codons.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003000.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	NM_003000.3	MANE Select	c.841T>G	p.Ter281Gluext*?	stop_lost	Exon 8 of 8	NP_002991.2	P21912
	SDHB	NM_001407361.1		c.787T>G	p.Ter263Gluext*?	stop_lost	Exon 8 of 8	NP_001394290.1	A0AAQ5BHD9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	ENST00000375499.8	TSL:1 MANE Select	c.841T>G	p.Ter281Gluext*?	stop_lost	Exon 8 of 8	ENSP00000364649.3	P21912
	SDHB	ENST00000714034.1		c.886T>G	p.Ter296Gluext*?	stop_lost	Exon 9 of 9	ENSP00000519325.1	A0AAQ5BHC9
	SDHB	ENST00000925621.1		c.835T>G	p.Ter279Gluext*?	stop_lost	Exon 8 of 8	ENSP00000595680.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251338 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454980 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724324

African (AFR) AF: 0.00 AC: 0 AN: 33340

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105868

Other (OTH) AF: 0.00 AC: 0 AN: 60162

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.76
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		6.8
Vest4		0.21
GERP RS		5.4
Mutation Taster		=84/116	disease causing

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

Other links and lift over

dbSNP: rs1316826258; hg19: chr1-17345378;