rs770622939

Positions:

• chr1-17023978-T-A
• chr1-17023978-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_003000.3(SDHB):​c.637A>T​(p.Met213Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000686 in 1,457,406 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M213R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• 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 Uncertain_significance. Variant got 4 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, 15 uncertain in NM_003000.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.637A>T	p.Met213Leu	missense_variant	6/8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.583A>T	p.Met195Leu	missense_variant	6/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.637A>T	p.Met213Leu	missense_variant	6/8	1	NM_003000.3	ENSP00000364649.3
SDHB	ENST00000491274.6	c.595A>T	p.Met199Leu	missense_variant	6/8	5		ENSP00000480482.2
SDHB	ENST00000463045.3	c.466A>T	p.Met156Leu	missense_variant	6/8	3		ENSP00000481376.2
SDHB	ENST00000485515.5	n.571A>T		non_coding_transcript_exon_variant	6/7	5		ENSP00000519322.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251322 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135842

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1457406 Hom.: 0 Cov.: 30 AF XY: 0.00000689 AC XY: 5 AN XY: 725200

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000632

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 03, 2023

This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 213 of the SDHB protein (p.Met213Leu). This variant is present in population databases (rs770622939, gnomAD 0.0009%). This missense change has been observed in individual(s) with pheochromocytoma and/or paraganglioma (PMID: 34906457). ClinVar contains an entry for this variant (Variation ID: 826367). 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 not expected to disrupt SDHB protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a cohort of individuals with pheochromocytomas and paragangliomas (PCC/PGL) in published literature (PMID: 34906457); This variant is associated with the following publications: (PMID: 34906457) -

Gastrointestinal stromal tumor Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 15, 2023

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2024

The p.M213L variant (also known as c.637A>T), located in coding exon 6 of the SDHB gene, results from an A to T substitution at nucleotide position 637. The methionine at codon 213 is replaced by leucine, an amino acid with highly similar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with SDHB-related paraganglioma-pheochromocytoma syndrome (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Uncertain	0.72	D;.
Eigen	Benign	-0.24
Eigen_PC	Benign	0.013
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	0.27	N;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.2	N;.
REVEL	Pathogenic	0.68
Sift	Benign	0.70	T;.
Sift4G	Benign	1.0	T;T
Polyphen		0.10	B;.
Vest4		0.76
MutPred		0.56		Gain of helix (P = 0.1736);.;
MVP		0.90
MPC		0.23
ClinPred		0.47	T
GERP RS		5.5
Varity_R		0.28
gMVP		0.85

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: rs770622939; hg19: chr1-17350473;