rs267607032

chr1-17028605-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_003000.3(SDHB):c.418G>T(p.Val140Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,614,050 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. V140D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 4.46

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 14 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_003000.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-17028604-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2562717.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 1-17028605-C-A is Pathogenic according to our data. Variant chr1-17028605-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17028605-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHB	NM_003000.3	c.418G>T	p.Val140Phe	missense_variant	4/8	ENST00000375499.8
SDHB	NM_001407361.1	c.369+49G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHB	ENST00000375499.8	c.418G>T	p.Val140Phe	missense_variant	4/8	1	NM_003000.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152206 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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251418 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135882

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461844 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727226

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

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: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paragangliomas 4 Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 07, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 28, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 24, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:20503330, 20583550, 30050099, 16912137, 19576851]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 25, 2022	This missense variant replaces valine with phenylalanine at codon 140 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over twenty individuals affected with hereditary paragangliomas/pheochromocytomas, including children (PMID: 16912137, 18840642, 19189136, 19215943, 19927285, 20418362, 20503330, 20583550, 25683602, 26236513, 27171833, 28503760, 29951630, 20503330). This variant has been shown to segregate with disease in two unrelated families (PMID: 20503330, 20583550). Multiple carrier individuals from one of these families were unaffected with SDHB-associated disease. One study has reported detection of this variant in 16 family members of 9 index patients, however, only 5 of these 16 family members were found to have paragangliomas/pheochromocytomas (PMID: 28374168). This study suggested that the penetrance of this variant is 50% at age 38. This variant has been identified in 3/251418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:3

Pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	The penetrance of the disease in SDHB mutations carriers is not 100%, it is about 45-50%. There apparently are other factors contributing to disease development, however those are yet not known. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 28, 2022	Variant summary: SDHB c.418G>T (p.Val140Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251978 control chromosomes. c.418G>T has been reported in the literature in multiple individuals affected with features of Hereditary Paraganglioma-Pheochromocytoma Syndrome and a reduced penetrance in some families (examples, Brouwers_2006, Meyer-Rochow_2008, Trimmers_2007, Santiago_2010, Lodish_2010, Ricketts_2010, Majumdar_2010, Muth_2012, Prodanov_2009, Schimke_2010, Bayley_2010). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function has been ascertained. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 08, 2023	This missense variant replaces valine with phenylalanine at codon 140 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over twenty individuals affected with hereditary paragangliomas/pheochromocytomas, including children (PMID: 16912137, 18840642, 19189136, 19215943, 19927285, 20418362, 20503330, 20583550, 25683602, 26236513, 27171833, 28503760, 29951630, 20503330). This variant has been shown to segregate with disease in two unrelated families (PMID: 20503330, 20583550). Multiple carrier individuals from one of these families were unaffected with SDHB-associated disease. One study has reported detection of this variant in 16 family members of 9 index patients, however, only 5 of these 16 family members were found to have paragangliomas/pheochromocytomas (PMID: 28374168). This study suggested that the penetrance of this variant is 50% at age 38. This variant has been identified in 3/251418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2023	Observed frequently in unrelated patients from different ethnic backgrounds with SDHB-related tumors, several of whom had tumor studies consistent with pathogenic variants in this gene (PMID: 18840642, 19189136, 19576851, 19927285, 20503330, 22588707, 25683602, 29204718, 30050099); Segregates with disease in many affected individuals in several kindreds referred for genetic testing at GeneDx and in published literature (PMID: 20583550, 20503330); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26236513, 20418362, 22588707, 29386252, 34906457, 30050099, 16912137, 20503330, 19927285, 20583550, 19189136, 18840642, 19576851, 22270996, 19802898, 25025441, 25683602, 26273102, 27910947, 27171833, 28374168, 28490599, 28748451, 29204718, 28503760, 29951630, 28152038, 32062700, 32035780, 32741965, 30787465, Hochfelder[abstract], 34703596, 20213850, 34308104, 27535533) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 16, 2022	The p.V140F pathogenic mutation (also known as c.418G>T), located in coding exon 4 of the SDHB gene, results from a G to T substitution at nucleotide position 418. The valine at codon 140 is replaced by phenylalanine, an amino acid with highly similar properties. In one study, this mutation was detected in a 13-year-old boy diagnosed with an abdominal paraganglioma whose mother (also a carrier) was diagnosed with a thoracic paraganglioma at the age of 14 (Santiago AH et al. J. Pediatr. Endocrinol. Metab., 2010 Apr;23:419-22). In another study, two siblings were found to be carriers of this alteration, a 55-year-old woman and her 49-year-old brother, both of whom were diagnosed with a paraspinal paraganglioma. Their mother, however, was 76 years old and unaffected with cancer, suggesting reduced penetrance. Of note, this family also had a deceased sibling who was diagnosed with a neuroblastoma as an infant, metastatic extra adrenal sympathetic paragangliomas reminiscent of pheochromocytomas as a young adult, and renal cell carcinoma as an adult. It is not known whether this sibling was a carrier of this alteration (Schimke RN et al. Am. J. Med. Genet. A, 2010 Jun;152A:1531-5). A retrospective study looking at genotype-phenotype correlations of SDHB mutation carriers identified 4 patients with this variant; however, only one of these patients had PGL/PCC, again suggesting reduced penetrance (Rijken JA et al. Clin. Genet. 2018 Jan;93(1):60-66). In a recent study, 16 family members of 9 index patients with this mutation were found to carry it; however, only 5 of these family members were found to have disease when they underwent screening for PGL/PCC. This study suggests that the penetrance of p.V140P is 50% at age 38 (Jochmanova I et al. J. Cancer Res. Clin. Oncol., 2017 Aug;143:1421-1435). This variant has also been reported in other cases of childhood metastatic paragangliomas where the carrier parent has been unaffected, again suggesting possible decreased penetrance (Prodanov T et al. Pediatr. Nephrol., 2009 Jun;24:1239-42; Majumdar S et al. Pediatr Blood Cancer, 2010 Mar;54:473-5). In addition, this mutation was detected in an individual with pheochromocytoma whose tumor demonstrated absent SDHB staining on immunohistochemistry (van Nederveen FH et al. Lancet Oncol., 2009 Aug;10:764-71). This alteration has also been identified in 2/27 patients with urinary bladder paraganglioma (Martucci VL et al. Urol. Oncol., 2015 Apr;33:167.e13-20). Based on internal structural analysis, this mutation is anticipated to result in a significant decrease in structural stability (Inaoka DK et al. Int J Mol Sci, 2015 Jul;16:15287-308). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 140 of the SDHB protein (p.Val140Phe). This variant is present in population databases (rs267607032, gnomAD 0.003%). This missense change has been observed in individuals with paraganglioma (PGL) and malignant PGL (PMID: 16912137, 19189136, 19802898, 19927285, 20503330, 20583550, 26236513). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18454). 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%. For these reasons, this variant has been classified as Pathogenic. -

Gastrointestinal stromal tumor Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.2	H;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.3	D;.;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.92
MutPred		0.73		Loss of methylation at K137 (P = 0.1188);.;.;
MVP		0.97
MPC		0.80
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs267607032; hg19: chr1-17355100;