1-17033086-A-G

Position:

• chr1-17033086-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_003000.3(SDHB):​c.260T>C​(p.Leu87Ser) variant causes a missense 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L87V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.19

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]

SDHB (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_003000.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 1-17033086-A-G is Pathogenic according to our data. Variant chr1-17033086-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 178686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17033086-A-G is described in Lovd as [Likely_pathogenic]. Variant chr1-17033086-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.260T>C	p.Leu87Ser	missense_variant	3/8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.260T>C	p.Leu87Ser	missense_variant	3/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.260T>C	p.Leu87Ser	missense_variant	3/8	1	NM_003000.3	ENSP00000364649.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

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

Feb 01, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 87 of the SDHB protein (p.Leu87Ser). This missense change has been observed in individuals with paragangliomas and/or pheochromocytomas (PMID: 11404820, 12807974, 15328326, 19454582, 22517557; Invitae). For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHB protein function. ClinVar contains an entry for this variant (Variation ID: 178686). This variant is also known as 394T>C (L88S) and 263T>C (L88S). -

Paragangliomas 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 08, 2023

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 12807974, 31492822, 15328326]. This variant is expected to disrupt protein structure [internal Myriad data]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2022

The p.L87S pathogenic mutation (also known as c.260T>C), located in coding exon 3 of the SDHB gene, results from a T to C substitution at nucleotide position 260. The leucine at codon 87 is replaced by serine, an amino acid with dissimilar properties. This alteration was originally reported in one study that analyzed 24 cases of sporadic pheochromocytomas, and this alteration was detected in a 55-year-old woman with a personal history of an adrenal pheochromocytoma (Astuti D et al. Am. J. Hum. Genet., 2001 Jul;69:49-54). In a subsequent study, this mutation was observed in three families with either adrenal or extra-adrenal phenochromocytoma. In one family with history of extra-adrenal phenochromocytoma, six individuals, including the index case, were found to carry this mutation. In addition, this mutation was not detected in 300 control samples from white healthy blood donors (Neumann HP et al. JAMA, 2004 Aug;292:943-51). The mutation was also reported in 1 out of 445 patients with paragangliomas, and it was not detected in 200 control chromosomes sampled (Burnichon N et al. J. Clin. Endocrinol. Metab., 2009 Aug;94:2817-27). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Sun F et al. Cell, 2005 Jul;121:1043-57). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 16, 2013

The Leu87Ser variant in SDHB has been reported in at least 6 individuals with pa raganglioma/pheochromocytoma, one of which progressed into malignant disease (Bu rnichon 2009, Buffet 2012). In addition, this variant has been identified in 1 i n >13,000 control chromosomes (Astuti 2001, Neumann 2004, Burnichon 2009, NHLBI Exome Sequencing Project: http://evs.gs.washington.edu/EVS/). Please note that f or diseases with clinical variability, reduced penetrance, or recessive inherita nce, pathogenic variants may be present at a low frequency in the general popula tion. Computational analyses (biochemical amino acid properties, conservation, A lignGVGD, PolyPhen2, and SIFT) suggest that the Leu87Ser variant may impact the protein, though this information is not predictive enough to determine pathogeni city. In summary, this variant is likely to be pathogenic based on published dat a and a low allele frequency in control chromosomes, though additional studies a re required to fully establish its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.5	H;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.4	D;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.71		Gain of disorder (P = 0.0032);.;.;
MVP		0.99
MPC		0.82
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.93

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: rs727504457; hg19: chr1-17359581;