rs1131691061

Positions:

• chr1-17054017-C-T

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.3G>A​(p.Met1?) variant causes a start lost 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 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 4.14

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]

SDHB (HGNC:):

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 428918
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-17054017-C-T is Pathogenic according to our data. Variant chr1-17054017-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 428932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17054017-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.3G>A	p.Met1?	start_lost	1/8	1	NM_003000.3	ENSP00000364649.3
SDHB	ENST00000466613.2	n.15G>A		non_coding_transcript_exon_variant	1/3	2
SDHB	ENST00000485515.5	n.-10G>A		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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paragangliomas 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 08, 2023	This variant results in the loss of the translation start codon (methionine at codon 1) of the SDHB gene. This variant is expected to disrupt the expression of the full-length SDHB protein. The next in-frame methionine occurs at codon 58, but it is not known if a functional SDHB protein product can be produced using p.Met58 as an alternative translation start site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with pheochromocytoma/paraganglioma (PMID: 19351833, 22241717, 23407919, 27279923, 27279923, 32688340). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 12, 2023	This variant is considered pathogenic. This variant is located within the gene translation start codon (p.Met1?) and is predicted to result in abnormal protein translation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:28503760, 32688340, 24096523, 28374168]. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2023	Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Identified in multiple individuals with a personal and/or family history of SDHB-related tumors in published literature (Neumann et al., 2009; Piccini et al., 2012; Sjursen et al., 2013; Bayley et al., 2020; Main et al., 2020); This variant is associated with the following publications: (PMID: 19351833, 23407919, 31492822, 32688340, 24096523, 22241717, 27279923) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	SDHB: PS4, PM2, PS1:Moderate, PVS1:Moderate -

Pheochromocytoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Feb 09, 2022

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2021

Disruption of the initiator codon has been observed in individuals with paragangliomas, pheochromocytomas and renal cell carcinomas (PMID: 19351833, 22241717, 23407919, 23512077, 24096523, 25047027, 27279923, 28490599, 29951630). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg46 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12618761, 14500403, 15328326, 16314641, 17102082, 18362451, 23083876, 23282968). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 428932). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the SDHB mRNA. The next in-frame methionine is located at codon 58. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 24, 2017

The p.M1? variant (also known as c.3G>A), located in coding exon 1 of the SDHB gene, results from a G to A substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. This alteration has been detected in multiple individuals with paraganglioma and/or pheochromocytoma (Neumann HP et al. Cancer Res. 2009 Apr;69(8):3650-6; Piccini V et al. Endocr. Relat. Cancer 2012 Apr;19(2):149-55; Sjursen W et al. Fam. Cancer 2013 Sep;12(3):529-35; Papathomas TG et al. Eur. J. Endocrinol. 2014 Jan;170:1-12). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 08, 2023

This variant results in the loss of the translation start codon (methionine at codon 1) of the SDHB gene. This variant is expected to disrupt the expression of the full-length SDHB protein. The next in-frame methionine occurs at codon 58, but it is not known if a functional SDHB protein product can be produced using p.Met58 as an alternative translation start site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with pheochromocytoma/paraganglioma (PMID: 19351833, 22241717, 23407919, 27279923, 27279923, 32688340). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
PROVEAN	Benign	-0.72	N
REVEL	Pathogenic	0.68
Sift	Benign	0.084	T
Sift4G	Benign	0.15	T
Polyphen		0.53	P
Vest4		0.97
MutPred		0.99		Loss of disorder (P = 0.0317);
MVP		0.93
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.56

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: rs1131691061; hg19: chr1-17380512;