chr1-17028605-C-A

Position:

chr1-17028605-C-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 4.46

Variant links:

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 links:

SDHB (HGNC:):

SDHB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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 chr1-17028604-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	Protein	UniProt
SDHB	NM_003000.3 linkuse as main transcript	c.418G>T	p.Val140Phe	missense_variant	4/8	ENST00000375499.8	NP_002991.2	P21912
SDHB	NM_001407361.1 linkuse as main transcript	c.369+49G>T		intron_variant			NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8 linkuse as main transcript	c.418G>T	p.Val140Phe	missense_variant	4/8	1	NM_003000.3	ENSP00000364649.3		P21912

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

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:

AN:

251418

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135882

show subpopulations

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:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727226

show subpopulations

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:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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, 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. -
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. -

not provided

Pathogenic:2

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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 07, 2018	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 25, 2021	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

SDHB-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2024

The SDHB c.418G>T variant is predicted to result in the amino acid substitution p.Val140Phe. This variant was reported in multiple patients with paraganglioma (Brouwers et al. 2006. PubMed ID: 16912137; Niemeijer et al. 2017. PubMed ID: 28490599; Andrews et al. 2018. PubMed ID: 29386252; Rijken et al. 2018. PubMed ID: 29951630; Richter et al. 2018. PubMed ID: 30050099). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/18454/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;.;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.2

H;.;.

PrimateAI

Uncertain

0.70

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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