rs876659329

Positions:

• chr1-17044767-A-G
• chr1-17044767-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_003000.3(SDHB):​c.194T>C​(p.Leu65Pro) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L65F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.44

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 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 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 chr1-17044767-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 231737.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 1-17044767-A-G is Pathogenic according to our data. Variant chr1-17044767-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 412457.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-17044767-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.194T>C	p.Leu65Pro	missense_variant	2/8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.194T>C	p.Leu65Pro	missense_variant	2/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.194T>C	p.Leu65Pro	missense_variant	2/8	1	NM_003000.3	ENSP00000364649.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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

Dec 17, 2023

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 65 of the SDHB protein (p.Leu65Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with gastrointestinal stromal tumor, paraganglioma, and/or pheochromocytoma (PMID: 15328326; Invitae). ClinVar contains an entry for this variant (Variation ID: 412457). 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%. Experimental studies have shown that this missense change affects SDHB function (PMID: 22835832). This variant disrupts the p.Leu65 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been observed in individuals with SDHB-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.88	D;.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.0	D;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.98
MutPred		0.86		Loss of stability (P = 0.0213);.;.;
MVP		0.99
MPC		0.89
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.95
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: rs876659329; hg19: chr1-17371262;