rs570278423

Variant names:

• chr1-17033077-C-A
• rs570278423
• NM_003000.3:c.269G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-17033077-C-A
• chr1-17033077-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_003000.3(SDHB):​c.269G>T​(p.Arg90Leu) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 6.92

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 11 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 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 chr1-17033077-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201609.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=5}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 1-17033077-C-A is Pathogenic according to our data. Variant chr1-17033077-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1493254.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHB	NM_003000.3	c.269G>T	p.Arg90Leu	missense_variant	Exon 3 of 8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.269G>T	p.Arg90Leu	missense_variant	Exon 3 of 8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.269G>T	p.Arg90Leu	missense_variant	Exon 3 of 8	1	NM_003000.3	ENSP00000364649.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jun 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 90 of the SDHB protein (p.Arg90Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 1493254). 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 with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg90 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17102082, 23175444, 26269449). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Gastrointestinal stromal tumor;C1847319:Carney-Stratakis syndrome;C1861848:Paragangliomas 4;C5543176:Mitochondrial complex 2 deficiency, nuclear type 4 Uncertain:1

May 16, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastrointestinal stromal tumor Uncertain:1

Oct 16, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	H;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.3	D;.;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.97
MutPred		0.91		Gain of sheet (P = 0.0344);.;.;
MVP		0.96
MPC		0.77
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		Position offset: -17

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

Publications

LitVar

Other links and lift over

dbSNP: rs570278423; hg19: chr1-17359572;