rs1131691049

Positions:

• chr1-17054019-T-A
• chr1-17054019-T-C

Variant summary

Our verdict is Pathogenic. Variant got 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

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_003000.3 (SDHB) was described as [Pathogenic] in ClinVar as 428932
• 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 id is 428918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.1A>T	p.Met1?	initiator_codon_variant	1/8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.1A>T	p.Met1?	initiator_codon_variant	1/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.1A>T	p.Met1?	initiator_codon_variant	1/8	1	NM_003000.3	ENSP00000364649.3
SDHB	ENST00000466613.2	n.13A>T		non_coding_transcript_exon_variant	1/3	2
SDHB	ENST00000485515.5	n.-12A>T		upstream_gene_variant		5		ENSP00000519322.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2023

This sequence change affects the initiator methionine of the SDHB mRNA. The next in-frame methionine is located at codon 58. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SDHB protein in which other variant(s) (p.Arg46Gln) have been determined to be pathogenic (PMID: 12618761, 14500403, 15328326, 16314641, 17102082, 18362451, 23083876, 23282968). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 428918). Disruption of the initiator codon has been observed in individuals with paragangliomas, pheochromocytomas and renal cell carcinomas (PMID: 23512077, 24096523, 27279923, 28374168, 32741965). This variant is not present in population databases (gnomAD no frequency). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 25, 2014

The p.M1L mutation (also known as c.1A>T) is located in exon 1 of the SDHB gene and results from an A to T substitution at nucleotide position 1. This changes the amino acid from methionine to leucine at the initiation codon. Since sequence variations that modify the initiation codon (ATG) are expected to cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med 2008;10:294). -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Section on Medical Neuroendocrinolgy, National Institutes of Health

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Computational scores

Source: dbNSFP v4.3

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
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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.45
gMVP		0.49

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: rs1131691049; hg19: chr1-17380514;