NM_003000.3:c.1A>T

Variant names:

• chr1-17054019-T-A
• rs1131691049
• NM_003000.3:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_003000.3(SDHB):​c.1A>T​(p.Met1?) variant causes a initiator codon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHB NM_003000.3 initiator_codon
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.19
• Publications: 4 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: Genomics England PanelApp, G2P, Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 45 pathogenic variants. Next in-frame start position is after 58 codons. Genomic position: 17044789. Lost 0.204 part of the original CDS.
• PS1: Another start lost variant in NM_003000.3 (SDHB) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-17054019-T-A is Pathogenic according to our data. Variant chr1-17054019-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 428918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1A>T	p.Met1?	initiator_codon	Exon 1 of 8	NP_002991.2	P21912
	SDHB	NM_001407361.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 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.1A>T	p.Met1?	initiator_codon	Exon 1 of 8	ENSP00000364649.3	P21912
	SDHB	ENST00000714031.1		c.-267A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000519321.1	A0A087WXX8
	SDHB	ENST00000714037.1		c.-171A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000519328.1	A0AAQ5BHB4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Hereditary pheochromocytoma-paraganglioma (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	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.047
Eigen_PC	Benign	0.058
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
PhyloP100		4.2
PROVEAN	Benign	-0.43	N
REVEL	Pathogenic	0.69
Sift	Benign	0.40	T
Sift4G	Benign	0.43	T
Polyphen		0.17	B
Vest4		0.93
MutPred		0.98		Loss of catalytic residue at M1 (P = 0.0071)
MVP		0.90
ClinPred		0.98	D
GERP RS		5.2
PromoterAI		-0.92	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.45
gMVP		0.49
Mutation Taster		=11/189	disease causing (ClinVar)

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: rs1131691049; hg19: chr1-17380514;