rs587782904

chr1-17033143-C-T

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.203G>A(p.Cys68Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,457,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. C68R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SDHB NM_003000.3 missense, splice_region
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.93

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 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in NM_003000.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863
• PP5: Variant 1-17033143-C-T is Pathogenic according to our data. Variant chr1-17033143-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17033143-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.203G>A	p.Cys68Tyr	missense_variant, splice_region_variant	3/8	ENST00000375499.8
SDHB	NM_001407361.1	c.203G>A	p.Cys68Tyr	missense_variant, splice_region_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.203G>A	p.Cys68Tyr	missense_variant, splice_region_variant	3/8	1	NM_003000.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457650 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725424

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 02, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. A structural analysis predicts that this missense change located near the 2Fe-2S cluster may affect proper SDHB protein conformation or folding (PMID: 22904323). In addition, general algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has been observed in individual(s) with clinical features of hereditary paraganglioma-pheochromocytoma syndrome (PMID: 22492777, 19576851, 21520333, 27279923, 30877234, 22517557, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 68 of the SDHB protein (p.Cys68Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 17, 2019

The p.C68Y variant (also known as c.203G>A), located in coding exon 3 of the SDHB gene, results from a G to A substitution at nucleotide position 203. The cysteine at codon 68 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple patients with paragangliomas and pheochromocytomas (Loriot et al. J Clin Endocrinol Metab. 2012 Jun;97(6):E954-62; Burnichon N et al. Hum. Mol. Genet. 2011 Oct;20:3974-85; Bennedbæk M et al. Hered Cancer Clin Pract. 2016 Jun;14:13). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.;T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-9.5	D;.;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0010	D;.;.
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.96
MutPred		0.33		Loss of methylation at K67 (P = 0.035);.;.;
MVP		1.0
MPC		0.85
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.91
gMVP		0.86

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: rs587782904; hg19: chr1-17359638; COSMIC: COSV100973316;