1-17053988-C-T

Variant names:

• chr1-17053988-C-T
• rs111430410
• NM_003000.3:c.32G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong 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 Likely benign (★★). 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: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:2 B:14
• Conservation: PhyloP100: 1.84
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• Carney-Stratakis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• pheochromocytoma/paraganglioma syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• mitochondrial complex 2 deficiency, nuclear type 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 54 uncertain in NM_003000.3
• 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 Benign/Likely_benign. ClinVar VariationId is 36768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003000.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	NM_003000.3	MANE Select	c.32G>A	p.Arg11His	missense	Exon 1 of 8	NP_002991.2
	SDHB	NM_001407361.1		c.32G>A	p.Arg11His	missense	Exon 1 of 8	NP_001394290.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	ENST00000375499.8	TSL:1 MANE Select	c.32G>A	p.Arg11His	missense	Exon 1 of 8	ENSP00000364649.3
	SDHB	ENST00000714034.1		c.32G>A	p.Arg11His	missense	Exon 1 of 9	ENSP00000519325.1
	SDHB	ENST00000485515.6	TSL:5	c.32G>A	p.Arg11His	missense	Exon 1 of 8	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

GnomAD2 exomes AF: 0.000391 AC: 95 AN: 242914 AF XY: 0.000340

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 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

African (AFR) AF: 0.00676 AC: 226 AN: 33454

American (AMR) AF: 0.000314 AC: 14 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111634

Other (OTH) AF: 0.000747 AC: 45 AN: 60246

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

African (AFR) AF: 0.00601 AC: 250 AN: 41572

American (AMR) AF: 0.000653 AC: 10 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000798 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: Benign/Likely benign

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jan 28, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 10, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 05, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Pheochromocytoma/paraganglioma syndrome 4 Uncertain:1 Benign:1

Jan 16, 2018

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Apr 24, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

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.

Hereditary cancer-predisposing syndrome Benign:2

Oct 01, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Feb 17, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Section on Medical Neuroendocrinolgy, National Institutes of Health

Significance: Pathogenic

Review Status: flagged submission

Collection Method: research

Papillary renal cell carcinoma type 1 Uncertain:1

Jun 01, 2014

CSER _CC_NCGL, University of Washington

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: research

Pheochromocytoma Benign:1

Mar 11, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 11, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided Benign:1

Sep 21, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Paraganglioma;C0031511:Pheochromocytoma Benign:1

Jul 10, 2020

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SDHB-related disorder Benign:1

Oct 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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:Pheochromocytoma/paraganglioma syndrome 4;C5543176:Mitochondrial complex 2 deficiency, nuclear type 4 Benign:1

Mar 04, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.8
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
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.49
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs111430410; hg19: chr1-17380483;