rs397516833

Positions:

• chr1-17028737-C-G

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.287-1G>C variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHB NM_003000.3 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 7.23

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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-17028737-C-G is Pathogenic according to our data. Variant chr1-17028737-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 44642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17028737-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.287-1G>C		splice_acceptor_variant		ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.287-1G>C		splice_acceptor_variant			NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.287-1G>C		splice_acceptor_variant		1	NM_003000.3	ENSP00000364649	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 04, 2024	This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. A different variant at the same splice site has been reported in association with disease and is independently classified as likely pathogenic or pathogenic. This variant has been reported in multiple individuals with paraganglioma (PMID: 17200167, 18382370, 23072324, 25371406, 36786389, 28179334, 27549546, 30050099, 28374168, 36387130). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2021	Variant summary: SDHB c.287-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251204 control chromosomes. c.287-1G>C has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (example, Timmers_2007, Jafri_2013, Fishbein_2013, Del Forno_2016, LaDuca_2017, Rinelli_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 06, 2012	The 287-1G>C variant in SDHB has been reported in one individual with paragangli oma and segregated with disease in one affected relative in that family (Timmers 2007). This variant has also been identified in a benign paraganglioma sample ( Klein 2008). This variant occurs in the invariant region (+/- 1,2) of the splic e consensus sequence and is predicted to cause altered splicing leading to an ab normal or absent protein. In summary, the 287-1G>C variant is likely pathogenic, though additional studies are required to fully establish its clinical signific ance. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SDHB: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2017	This variant is denoted SDHB c.287-1G>C or IVS3-1G>C and consists of a G>C nucleotide substitution at the -1 position of intron 3 of the SDHB gene. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in multiple cases with malignant paraganglioma, at least one of which showed absence of SDHB staining by immunohistochemistry (Timmers 2007, He 2009, Fishbein 2013, Jafri 2013, Sue 2015, Del Forno 2016, Gupta 2016, Jochmanova 2017). Based on currently available evidence, we consider SDHB c.287-1G>C to be a pathogenic variant. -

Paragangliomas 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 02, 2024	This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30050099, 31883676, 32035780, 31492822, 35460558]. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 02, 2017	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 24, 2023

This sequence change affects an acceptor splice site in intron 3 of the SDHB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SDHB are known to be pathogenic (PMID: 19454582, 19802898). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with paraganglioma-pheochromocytoma syndromes (PMID: 17200167, 18382370, 19454582, 27549546, 30050099, 34750850; Invitae). This variant is also known as IVS3-1 G>C. ClinVar contains an entry for this variant (Variation ID: 44642). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2022

The c.287-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide upstream from coding exon 4 of the SDHB gene. This alteration has been reported in an individual with PGL-PCC and a positive family history (Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar;92:779-86). This alteration was also reported in three other patients with PGL-PCC (Klein RD et al. Diagn. Mol. Pathol. 2008 Jun;17:94-100; Jafri M et al. Clin. Endocrinol. (Oxf) 2013 Jun;78:898-906; Sue M et al. Eur. J. Endocrinol. 2015 Feb;172:89-95). A similar alteration (c.278-2A>G) has been reported in several families with PGL-PCC (Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94:2817-27; Neumann HP et al. JAMA 2004 Aug;292:943-51). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	D
GERP RS		6.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.94		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516833; hg19: chr1-17355232;