rs781590955

chr1-17023974-T-Cchr1-17023974-T-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_003000.3(SDHB):c.641A>G(p.Gln214Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to 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. Q214H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHB NM_003000.3 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.14

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_003000.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-17023973-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 480788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 1-17023974-T-C is Pathogenic according to our data. Variant chr1-17023974-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 412493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.641A>G	p.Gln214Arg	missense_variant, splice_region_variant	6/8	ENST00000375499.8
SDHB	NM_001407361.1	c.587A>G	p.Gln196Arg	missense_variant, splice_region_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.641A>G	p.Gln214Arg	missense_variant, splice_region_variant	6/8	1	NM_003000.3	P1
SDHB	ENST00000491274.6	c.599A>G	p.Gln200Arg	missense_variant, splice_region_variant	6/8	5
SDHB	ENST00000463045.3	c.470A>G	p.Gln157Arg	missense_variant, splice_region_variant	6/8	3
SDHB	ENST00000485515.5	n.575A>G		splice_region_variant, non_coding_transcript_exon_variant	6/7	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 28, 2023

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 214 of the SDHB protein (p.Gln214Arg). This variant is not present in population databases (gnomAD no frequency). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 412493). This missense change has been observed in individuals with pheochromocytoma or paraganglioma (PMID: 24659481; Invitae). It has also been observed to segregate with disease in related individuals. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The p.Q214R variant (also known as c.641A>G), located in coding exon 6 of the SDHB gene, results from an A to G substitution at nucleotide position 641. The glutamine at codon 214 is replaced by arginine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with paraganglioma or pheochromocytoma (Kimura N et al. Endocr Relat Cancer, 2014 Jun;21:L13-6; Yonamine M et al. Cancers (Basel), 2021 Aug;13:; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). In addition, as a missense substitution this 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. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 23, 2023

The p.Gln214Arg variant in SDHB has been reported in 4 individuals with pheochromocytoma (PCC) or paraganglioma (PGG) and segregated with disease in 2 affected relatives from 1 family. Immunohistochemistry studies from tumors sampled from at least one of these individuals showed loss of expression of the SDHB protein (Kimura 2014 PMID: 24659481, Invitae pers. comm., Ambry pers. comm., ClinVar: Variation ID 412493). This variant was absent from large population studies. Computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary paraganglioma-pheochromocytoma syndrome. ACMG/AMP Criteria applied: PS4, PS3_Moderate, PM2_Supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.5	D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.95
MutPred		0.58		Gain of methylation at Q214 (P = 0.04);.;
MVP		0.99
MPC		0.72
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		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: rs781590955; hg19: chr1-17350469;