chr1-17024025-G-C

Position:

• chr1-17024025-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_003000.3(SDHB):​c.590C>G​(p.Pro197Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,664 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P197S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 8.96

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 18 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-17024026-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 845283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 1-17024025-G-C is Pathogenic according to our data. Variant chr1-17024025-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12779.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17024025-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.590C>G	p.Pro197Arg	missense_variant	6/8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.536C>G	p.Pro179Arg	missense_variant	6/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.590C>G	p.Pro197Arg	missense_variant	6/8	1	NM_003000.3	ENSP00000364649.3
SDHB	ENST00000491274.6	c.548C>G	p.Pro183Arg	missense_variant	6/8	5		ENSP00000480482.2
SDHB	ENST00000463045.3	c.419C>G	p.Pro140Arg	missense_variant	6/8	3		ENSP00000481376.2
SDHB	ENST00000485515.5	n.524C>G		non_coding_transcript_exon_variant	6/7	5		ENSP00000519322.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251186 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135770

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: 0.00000821 AC: 12 AN: 1461664 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727116

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 07, 2022	PP1_moderate, PP3, PP4, PM2, PS4_moderate -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 12, 2019	The SDHB c.590C>G; p.Pro197Arg variant (rs74315367) is reported in the literature in multiple individuals and families affected with hereditary paraganglioma/pheochromocytoma syndrome, though it has also been reported in several asymptomatic carriers (Astuti 2001, Lawrence 2004, Niemeijer 2017, Rijken 2018, Srirangalingam 2008). Another variant at this codon, p.Pro197Ser, is also reported in individuals with paragangliomas (Hermsen 2010, Lima 2007). The p.Pro197Arg variant is reported in ClinVar (Variation ID: 12779). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The proline at codon 197 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. While biochemical characterization of p.Pro197Arg variant protein showed no effect on SDH activity or association with SDHA protein, in silico analysis of this variant suggested defective electron transport and generation of reactive oxygen species (Kim 2015). Based on available information, the p.Pro197Arg variant is considered to be likely pathogenic. REFERENCES Astuti D et al. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet. 2001 Jul;69(1):49-54. Hermsen MA et al. Relevance of germline mutation screening in both familial and sporadic head and neck paraganglioma for early diagnosis and clinical management. Cell Oncol. 2010 Jan 1;32(4):275-83. Kim E et al. Structural and functional consequences of succinate dehydrogenase subunit B mutations. Endocr Relat Cancer. 2015 Jun;22(3):387-97. Lawrence JK et al. Familial paraganglioma: a novel presentation of a case and response to therapy with radiolabelled MIBG. Hormones (Athens). 2004 Apr-Jun;3(2):127-31. Lima J et al. High frequency of germline succinate dehydrogenase mutations in sporadic cervical paragangliomas in northern Spain: mitochondrial succinate dehydrogenase structure-function relationships and clinical-pathological correlations. J Clin Endocrinol Metab. 2007 Dec;92(12):4853-64. Niemeijer ND et al. The phenotype of SDHB germline mutation carriers: a nationwide study. Eur J Endocrinol. 2017 Aug;177(2):115-125. Rijken JA et al. Nationwide study of patients with head and neck paragangliomas carrying SDHB germline mutations. BJS Open. 2018 Feb 6;2(2):62-69. Srirangalingam U et al. Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B (SDH-B) gene mutation carriers. Clin Endocrinol (Oxf). 2008 Oct;69(4):587-96. -

Paragangliomas 4 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 14, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11404820, 32741965, 29623478, 23934599, 19576851, 28503760]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2001	- -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1 Other:1

Likely pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -
not provided, no classification provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 02, 2015	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2023

This variant disrupts the p.Pro197 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been observed in individuals with SDHB-related conditions (PMID: 20208144), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change does not substantially affect SDHB function (PMID: 18519664, 25972245, 28738844). 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. ClinVar contains an entry for this variant (Variation ID: 12779). This missense change has been observed in individuals with gastrointestinal stromal tumor, paraganglioma, and/or pheochromocytoma (PMID: 11404820, 14974914, 18419787, 21348866, 25047027, 26556299, 27542510, 28374168; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs74315367, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 197 of the SDHB protein (p.Pro197Arg). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The p.P197R pathogenic mutation (also known as c.590C>G), located in coding exon 6 of the SDHB gene, results from a C to G substitution at nucleotide position 590. The proline at codon 197 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in multiple individuals/multiple families diagnosed with paragangliomas and/or pheochromocytomas (Astuti D et al. Am. J. Hum. Genet. 2001 Jul;69:49-54; Gimenez-Roqueplo AP et al. J. Clin. Endocrinol. Metab. 2002 Oct;87:4771-4; Lawrence JK et al. Hormones (Athens) 2004. 3(2):127-31; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435; Jawed I et al. Cell. Mol. Neurobiol. 2018 Jul;38:1099-1106; Rijken JA et al. BJS Open. 2018 Apr;2:62-69), as well as an individual diagnosed with a GIST (Schrader KA et al. JAMA Oncol. 2016 Jan;2:104-11). In one study, PGL-PCC tumor studies of an individual known to carry the p.P197R alteration showed negative SDHB protein expression on IHC (van Nederveen FH et al. Lancet Oncol. 2009 Aug;10:764-71). Authors of one study showed that the p.P197R alteration led to mitochondrial expression levels and SDH enzyme activity levels similar to that of wild type cells in vitro; however structural modeling predicted this alteration would affect the function of the electron path in the electron transport chain (Kim E et al. Endocr. Relat. Cancer. 2015 Jun;22:387-97). Based on internal structural analysis, P197R introduces a large, positively-charged side-chain into a functionally critical region of SDHB, and is likely to disrupt both ubiquinone binding and reduction of ubiquinone (Sun F et al. Cell. 2005 Jul;121:1043-57; Yankovskaya V et al. Science. 2003 Jan;299:700-4; Guo J et al. J. Biol. Chem. 2003 Nov;278:47629-35). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Of note, this variant is also called p.P198R (c.724C>G) in some literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.2	H;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-8.0	D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.96		Gain of catalytic residue at P197 (P = 0.0672);.;
MVP		1.0
MPC		0.71
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.96

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: rs74315367; hg19: chr1-17350520;