rs1131691058

chr1-17022629-G-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_003000.3(SDHB):c.744C>G(p.Asn248Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. N248S) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.60

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 16 ACMG points.

• PM1: In a hotspot region, there are 6 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 1-17022629-G-C is Pathogenic according to our data. Variant chr1-17022629-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17022629-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.744C>G	p.Asn248Lys	missense_variant	7/8	ENST00000375499.8
SDHB	NM_001407361.1	c.690C>G	p.Asn230Lys	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.744C>G	p.Asn248Lys	missense_variant	7/8	1	NM_003000.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paraganglioma Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Mar 11, 2022

Data included in classification: Absent from gnomAD (PM2_mod) Phenotype data: UK family #1: Observed in proband with bilateral head and neck paragangliomas (PP4_mod) Revel score >0.7 (0.866) (PP3_sup) Within “hot region” for SDHB as defined in Garrett et al. 2021 (https://doi.org/10.1016/j.gim.2021.08.004). (amino acids 177-260) (PM1_mod) Data not included in classification: Observed in Garrett et al. 2021 (https://doi.org/10.1016/j.gim.2021.08.004). 1/6118 cases (likely same proband from UK family #1) Crystal structure of mitochondrial respiratory membrane protein complex II.Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M, Rao Z.Cell. 2005 Jul 1;121(7):1043-57.PMID:15989954 -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2023

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 248 of the SDHB protein (p.Asn248Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paraganglioma (PMID: 18551016, 34906457; Invitae). ClinVar contains an entry for this variant (Variation ID: 428929). 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%. 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2021

The p.N248K variant (also known as c.744C>G), located in coding exon 7 of the SDHB gene, results from a C to G substitution at nucleotide position 744. The asparagine at codon 248 is replaced by lysine, an amino acid with similar properties. This alteration has been previously described in multiple individuals diagnosed with paragangliomas and/or pheochromocytomas (Persu A et al. J. Hypertens., 2008 Jul;26:1395-401; Fishbein L et al. Ann Surg Oncol, 2013 May;20:1444-50; Papathomas TG et al. Mod. Pathol., 2015 Jun;28:807-21). Based on internal structural assessment, this variant introduces a positive charge near the quinone-reducing active site and affects the final electron transfer reaction (Sun F et al. Cell, 2005 Jul;121:1043-57; Liu J et al. Chem. Rev., 2014 Apr;114:4366-469). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.80	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.87		Gain of methylation at N248 (P = 0.009);
MVP		0.98
MPC		0.74
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.97

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: rs1131691058; hg19: chr1-17349124;