rs111430410

Positions:

• chr1-17053988-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_003000.3(SDHB):​c.32G>A​(p.Arg11His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00034 in 1,612,962 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R11C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:14
• Conservation: PhyloP100: 1.84

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007355809).
• BP6: Variant 1-17053988-C-T is Benign according to our data. Variant chr1-17053988-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 36768.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=1, Benign=5}. Variant chr1-17053988-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00171 (260/152326) while in subpopulation AFR AF= 0.00601 (250/41572). AF 95% confidence interval is 0.0054. There are 1 homozygotes in gnomad4. There are 130 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.32G>A	p.Arg11His	missense_variant	1/8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.32G>A	p.Arg11His	missense_variant	1/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.32G>A	p.Arg11His	missense_variant	1/8	1	NM_003000.3	ENSP00000364649.3
SDHB	ENST00000466613.2	n.44G>A		non_coding_transcript_exon_variant	1/3	2
SDHB	ENST00000485515.5	n.20G>A		non_coding_transcript_exon_variant	1/7	5		ENSP00000519322.1

Frequencies

GnomAD3 genomes AF: 0.00166 AC: 252 AN: 152208 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000391 AC: 95 AN: 242914 Hom.: 0 AF XY: 0.000340 AC XY: 45 AN XY: 132346

Gnomad AFR exome AF: 0.00521

Gnomad AMR exome AF: 0.000350

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: 0.00

Gnomad OTH exome AF: 0.000507

GnomAD4 exome AF: 0.000198 AC: 289 AN: 1460636 Hom.: 1 Cov.: 30 AF XY: 0.000183 AC XY: 133 AN XY: 726572

Gnomad4 AFR exome AF: 0.00676

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000747

GnomAD4 genome AF: 0.00171 AC: 260 AN: 152326 Hom.: 1 Cov.: 31 AF XY: 0.00175 AC XY: 130 AN XY: 74480

Gnomad4 AFR AF: 0.00601

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000352 Hom.: 0

Bravo AF: 0.00179

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000445 AC: 54

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2020	The p.Arg11His variant in SDHB is classified as benign because it has high allele frequency. Although, ithas been reported in 1 individual with bilateral renal cell carcinoma (Ricketts 2008 PMID: 18728283), 1 individual with a neuroendocrine tumor but whose tumor was positive for SDHB immunostaining (van Nederveen 2009 PMID: 19576851), and classified as a VUS by Amendola (2015 PMID: 25637381) and Dorschner (2013 PMID: 24055113), it was also identified in 0.55% (133/24062) African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 36768). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. ACMG/AMP Criteria applied: BA1, BS4. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2021	Variant summary: SDHB c.32G>A (p.Arg11His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 274908 control chromosomes, predominantly at a frequency of 0.0055 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 629 fold of the estimated maximal expected allele frequency for a pathogenic variant in SDHB causing Pheochromocytoma phenotype (8.8e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.32G>A has been reported in the literature in at least an individual affected with adrenal Pheochromocytoma. However, the authors classified the variant as likely benign based on normal succinate: fumarate ratio obtained from a mass spectrometry-based screening assay performed on patient derived tissue samples (Richter_2019). Six other ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 28, 2022	- -

Paragangliomas 4 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 24, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Jan 16, 2018	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 01, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Pathogenic, no assertion criteria provided

research

Section on Medical Neuroendocrinolgy, National Institutes of Health

-

- -

Papillary renal cell carcinoma type 1 Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Pheochromocytoma Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 11, 2022

Data included in classification: Allele frequency is above 1x10-4 in gnomAD (77/14092 alleles in African population, MAF 0.5%, 92/114849 = MAF of 0.08% across all populations in gnomAD) (BA1_SA) Data not included in classification: Revel score 0.627 Observed in 3 UK probands with phaeochromocytoma/paraganglioma, one of which head and neck. Also observed in UK proband with 3 renal carcinomas, all with loss of SDHB on IHC -

Paraganglioma Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 11, 2022

Data included in classification: Allele frequency is above 1x10-4 in gnomAD (77/14092 alleles in African population, MAF 0.5%, 92/114849 = MAF of 0.08% across all populations in gnomAD) (BA1_SA) Data not included in classification: Revel score 0.627 Observed in 3 UK probands with phaeochromocytoma/paraganglioma, one of which head and neck. Also observed in UK proband with 3 renal carcinomas, all with loss of SDHB on IHC -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 21, 2021

This variant is associated with the following publications: (PMID: 24092654, 28374168, 24055113, 25637381, 26332594, 22835832, 18728283, 19576851, 30050099) -

Paraganglioma;C0031511:Pheochromocytoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 10, 2020

This variant has been observed in a 52-year-old proband diagnosed with three primary renal cell carcinomas, bilateral disease, multiple renal cysts and single angiomyolipoma. This variant has also been observed in three unrelated (to our knowledge) diagnostic cases of PP/PGL (one of which has inner ear PGL). This variant has previously been reported in the literature in patients with bilateral renal cell carcinoma (PMID: 18728283) and neuroendocrine tumour (PMID: 19576851). Succinate:Fumarate ratio in tumour samples from a patient with this variant were observed to be within normal range, indicating neutral impact on protein function (PMID: 30050099) (BS3_supporting). This variant has been observed in 149/274308 total alleles in gnomAD; including 133/24062 African alleles (BS1_strong). Data included in classification: Functional data and control (gnomAD) data Data not included in classification: Incidence in literature and other reported probands In silico predictions (conflicting) -

Gastrointestinal stromal tumor Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

SDHB-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 23, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1847319:Carney-Stratakis syndrome;C1861848:Paragangliomas 4;C5543176:Mitochondrial complex 2 deficiency, nuclear type 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Pathogenic	0.16
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.0074	T
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.63
Sift	Benign	0.12	T
Sift4G	Benign	0.064	T
Polyphen		0.87	P
Vest4		0.29
MVP		0.92
MPC		0.32
ClinPred		0.048	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.49

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: rs111430410; hg19: chr1-17380483;