VCV000012792.93 - ClinVar

NM_003000.3(SDHB):c.487T>C (p.Ser163Pro)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(3); Benign(19); Likely benign(1)

23 out of 32 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003000.3(SDHB):c.487T>C (p.Ser163Pro)

Variation ID: 12792 Accession: VCV000012792.93

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p36.13 1: 17027802 (GRCh38) [ NCBI UCSC ] 1: 17354297 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 12, 2013	Jan 24, 2026	Nov 1, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_003000.3:c.487T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002991.2:p.Ser163Pro	missense
NC_000001.11:g.17027802A>G
NC_000001.10:g.17354297A>G
NG_012340.1:g.31369T>C
LRG_316:g.31369T>C
LRG_316t1:c.487T>C	LRG_316p1:p.Ser163Pro
	P21912:p.Ser163Pro

... more HGVS ... less HGVS

Protein change

S163P

Other names

p.S163P:TCT>CCT

Canonical SPDI

NC_000001.11:17027801:A:G

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00938 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00921

1000 Genomes Project 0.00938

Exome Aggregation Consortium (ExAC) 0.01254

The Genome Aggregation Database (gnomAD), exomes 0.01211

Trans-Omics for Precision Medicine (TOPMed) 0.00751

The Genome Aggregation Database (gnomAD) 0.00921

The Genome Aggregation Database (gnomAD) 0.00954

The Genome Aggregation Database (gnomAD), exomes 0.01360

Links

ClinGen: CA015910 UniProtKB: P21912#VAR_054382 OMIM: 185470.0015 dbSNP: rs33927012 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SDHB		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	1535	1665

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Cowden syndrome	Uncertain significance (1)	no assertion criteria provided	Aug 1, 2008	RCV000013633.30
not provided	Conflicting classifications of pathogenicity (5)	criteria provided, conflicting classifications	Nov 1, 2025	RCV000034688.51
not specified	Benign (12)	criteria provided, multiple submitters, no conflicts	Mar 4, 2025	RCV000122002.53
Hereditary cancer-predisposing syndrome	Benign (2)	criteria provided, multiple submitters, no conflicts	Sep 11, 2020	RCV000132153.12
Pheochromocytoma/paraganglioma syndrome 4	Conflicting classifications of pathogenicity (5)	criteria provided, conflicting classifications	Apr 24, 2023	RCV000202946.21
Gastrointestinal stromal tumor Pheochromocytoma Pheochromocytoma/paraganglioma syndrome 4	Benign (1)	criteria provided, single submitter	Feb 4, 2025	RCV000206861.18
Hereditary pheochromocytoma and paraganglioma	Benign (2)	criteria provided, multiple submitters, no conflicts	Jun 9, 2022	RCV000282667.14
Gastrointestinal stromal tumor	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jun 22, 2021	RCV000986263.10
Carney-Stratakis syndrome	Benign (1)	criteria provided, single submitter	Mar 6, 2018	RCV001099292.12
Malignant tumor of breast	Benign (1)	no assertion criteria provided	-	RCV001269360.9

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Feb 13, 2015) C Contributing to aggregate classification	criteria provided, single submitter (DGD Variant Analysis Guidelines)	Paragangliomas 4	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000257933.2 First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (Nov 21, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Pheochromocytoma/paraganglioma syndrome 4	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV000883134.1 First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely benign (May 28, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Gastrointestinal stromal tumor	Mendelics Accession: SCV001135202.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Benign (Mar 06, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Carney-Stratakis syndrome	Illumina Laboratory Services, Illumina Accession: SCV001255735.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: show This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Mar 06, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Hereditary Paraganglioma-Pheochromocytoma Syndromes	Illumina Laboratory Services, Illumina Accession: SCV000351418.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Apr 03, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not specified	Genetic Services Laboratory, University of Chicago Accession: SCV000596998.2 First in ClinVar: Aug 27, 2017 Last updated: Jun 13, 2020	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Benign (Sep 11, 2020) C Contributing to aggregate classification	criteria provided, single submitter (Sema4 Curation Guidelines)	Hereditary cancer-predisposing syndrome	Sema4, Sema4 Accession: SCV002527080.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022	Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Benign (May 08, 2017) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698135.3 First in ClinVar: Apr 21, 2018 Last updated: Dec 11, 2022	Publications: PubMed (12) PubMed: 14985401‚ 16322339‚ 16912137‚ 17102082‚ 17102083‚ 17298551‚ 17639058‚ 18551016‚ 18678321‚ 19399650‚ 19802898‚ 26092435 Comment: show Variant summary: The SDHB c.487T>C (p.Ser163Pro) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1523/121404 control chromosomes (21 homozygotes) at a frequency of 0.0125449, which largely exceeds the estimated maximal expected allele frequency of a pathogenic SDHB variant (0.0000009), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Apr 10, 2018) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000235633.8 First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023	Comment: show This variant is associated with the following publications: (PMID: 19215943, 16322339, 17298551, 16912137, 22995991, 19768395, 22584711, 19802898, 19399650, 22293219, 24735130, 20981092, 27153395, 18678321, 21979946, 25376524, 22938532, 22703879, 25694510, 23666964, 25333069, 24728327, 26071763, 17102082, 17102083, 22270996, 25695889, 17639058, 14985401, 26182300, 18419787, 19153209, 19522823, 19454582, 27279923, 27884173, 26092435, 28374168, 29386252, 30050099, 31019283) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Dec 23, 2014) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV000187226.8 First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024	Comment: show This alteration is classified as 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Feb 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Gastrointestinal stromal tumor Pheochromocytoma/paraganglioma syndrome 4 Pheochromocytoma Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000262194.9 First in ClinVar: Jan 31, 2016 Last updated: Mar 04, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Nov 16, 2016) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015)	not specified	Eurofins Ntd Llc (ga) Accession: SCV000702933.3 First in ClinVar: Dec 19, 2017 Last updated: Apr 13, 2025	Publications: PubMed (7) PubMed: 16322339‚ 18678321‚ 21979946‚ 22995991‚ 25333069‚ 25694510‚ 26092435 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SDHB Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed

Benign (Jun 22, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Gastrointestinal stromal tumor	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV005912663.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025	Publications: PubMed (4) PubMed: 16912137‚ 17636058‚ 22703879‚ 24728327 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Jun 09, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Hereditary pheochromocytoma and paraganglioma	Color Diagnostics, LLC DBA Color Health Accession: SCV004362272.2 First in ClinVar: Feb 14, 2024 Last updated: May 03, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Platform type: NGS

Benign (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	NOT SPECIFIED	PreventionGenetics, part of Exact Sciences Accession: SCV000309334.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Nov 01, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Pheochromocytoma/paraganglioma syndrome 4	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000782276.1 First in ClinVar: Dec 27, 2015 Last updated: Dec 27, 2015	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Nov 03, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002010044.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided

Benign (Apr 24, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pheochromocytoma/paraganglioma syndrome 4	Myriad Genetics, Inc. Accession: SCV004045350.2 First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023	Comment: show This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

benign (Sep 23, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Athena Diagnostics Criteria)	not specified	Athena Diagnostics Accession: SCV005622275.1 First in ClinVar: Jan 19, 2025 Last updated: Jan 19, 2025	Publications: PubMed (33) PubMed: 14985401‚ 16322339‚ 16912137‚ 17102082‚ 17102083‚ 17298551‚ 17639058‚ 18419787‚ 18502330‚ 18551016‚ 18678321‚ 19153209‚ 19215943‚ 19399650‚ 19522823‚ 19768395‚ 19802898‚ 20981092‚ 21979946‚ 22584711‚ 22703879‚ 22938532‚ 23666964‚ 24728327‚ 24735130‚ 25333069‚ 25376524‚ 25694510‚ 25695889‚ 26071763‚ 26182300‚ 27279923‚ 32688340 Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Benign (Mar 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not specified	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002552130.5 First in ClinVar: Jul 27, 2022 Last updated: Mar 11, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Nov 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV001147171.37 First in ClinVar: Feb 03, 2020 Last updated: Jan 11, 2026	Comment: show SDHB: BS1, BS2 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 170

Benign (Dec 26, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Not specified	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV007321607.1 First in ClinVar: Jan 17, 2026 Last updated: Jan 17, 2026	Comment: show BS1, BS2 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 15

Benign (Mar 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	not provided	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV000605078.5 First in ClinVar: Sep 28, 2017 Last updated: Jan 24, 2026	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Aug 01, 2008) N Not contributing to aggregate classification	no assertion criteria provided	RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE	OMIM Accession: SCV000033880.4 First in ClinVar: Apr 04, 2013 Last updated: Sep 04, 2016	Publications: PubMed (2) PubMed: 18678321‚ 19368708 Hamosh, A. Personal Communication. (more...) Hamosh, A. Personal Communication. 2018. Baltimore, Md. Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: This variant, formerly titled COWDEN SYNDROME 2, has been reclassified based on a review of the ExAC database by Hamosh (2018). In 2 women with … (more) This variant, formerly titled COWDEN SYNDROME 2, has been reclassified based on a review of the ExAC database by Hamosh (2018). In 2 women with a Cowden-like phenotype (see 158350), Ni et al. (2008) identified a heterozygous ser163-to-pro (S163P) substitution in the SDHB gene. This mutation was not found in 700 control subjects. This mutation was associated with increased manganese superoxide dismutase function, increased reactive oxygen species, and a 2.7-fold change in AKT expression and 1.7-fold increase in MAPK expression. The patients, 29 and 54 years old, had thyroid cancer, and both had a family history of breast cancer and papillary thyroid carcinoma. Bayley (2011) commented that the findings of Ni et al. (2008) require independent confirmation, and suggested that functional studies of the SDH variants are essential before recommendations can be made for appropriate genetic counseling. Hamosh (2018) found that the S163P variant was present in heterozygous state in 1,523 of 121,404 alleles and in 21 homozygotes, with an allele frequency of 0.01254, in the ExAC database (July 11, 2018). (less)

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	Breast Cancer	Center of Medical Genetics and Primary Health Care Accession: SCV001448699.1 First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001807023.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Jul 13, 2012) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000043485.2 First in ClinVar: Apr 12, 2013 Last updated: Jun 08, 2025	Publications: PubMed (1) PubMed: 22703879 Comment: show Converted during submission from no known pathogenicity to Benign. (less) Observation: 1 Collection method: research Allele origin: germline Affected status: no more Observation 1 Collection method: research Allele origin: germline Affected status: no Number of individuals with the variant: 7 Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less) Platform type: High-Throughput DNA Sequencing Platform name: Illumina GAIIx

Benign (Mar 23, 2016) N Not contributing to aggregate classification	no assertion criteria provided	Pheochromocytoma/paraganglioma syndrome 4	Counsyl Accession: SCV000488422.3 First in ClinVar: Dec 27, 2015 Last updated: Jun 29, 2025	Publications: PubMed (3) PubMed: 14985401‚ 21979946‚ 23666964 Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001743804.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001922351.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (-) N Not contributing to aggregate classification	no assertion criteria provided	not specified	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001959772.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

not provided (Sep 19, 2013) N Not contributing to aggregate classification	no classification provided	AllHighlyPenetrant	ITMI Accession: SCV000086213.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation: 7 Observation 1 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Whole_cohort Platform type: next-gen sequencing Platform name: Complete Genomics Observation 2 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: African Platform type: next-gen sequencing Platform name: Complete Genomics Observation 3 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: African_European Platform type: next-gen sequencing Platform name: Complete Genomics Observation 4 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Central_Asian Platform type: next-gen sequencing Platform name: Complete Genomics Observation 5 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: East_Asian Platform type: next-gen sequencing Platform name: Complete Genomics Observation 6 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: European Platform type: next-gen sequencing Platform name: Complete Genomics Observation 7 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Hispanic Platform Type: next-gen sequencing Platform Name: Complete Genomics

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

Variant summary: The SDHB c.487T>C (p.Ser163Pro) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 1523/121404 control chromosomes (21 homozygotes) at a frequency of 0.0125449, which largely exceeds the estimated maximal expected allele frequency of a pathogenic SDHB variant (0.0000009), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign.

Comment:

This variant is associated with the following publications: (PMID: 19215943, 16322339, 17298551, 16912137, 22995991, 19768395, 22584711, 19802898, 19399650, 22293219, 24735130, 20981092, 27153395, 18678321, 21979946, 25376524, 22938532, 22703879, 25694510, 23666964, 25333069, 24728327, 26071763, 17102082, 17102083, 22270996, 25695889, 17639058, 14985401, 26182300, 18419787, 19153209, 19522823, 19454582, 27279923, 27884173, 26092435, 28374168, 29386252, 30050099, 31019283)

Comment:

This alteration is classified as 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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genotype-phenotype associations in PPGLs in 59 patients with variants in SDHX genes.	Main AM	Endocrine connections	2020	PMID: 32688340
Identification of eight novel SDHB, SDHC, SDHD germline variants in Danish pheochromocytoma/paraganglioma patients.	Bennedbæk M	Hereditary cancer in clinical practice	2016	PMID: 27279923
Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond.	Hansford S	JAMA oncology	2015	PMID: 26182300
Identification of cancer predisposition variants in apparently healthy individuals using a next-generation sequencing-based family genomics approach.	Karageorgos I	Human genomics	2015	PMID: 26092435
Coexistence of paraganglioma/pheochromocytoma and papillary thyroid carcinoma: a four-case series analysis.	Bugalho MJ	Familial cancer	2015	PMID: 26071763
Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice.	Xekouki P	The Journal of clinical endocrinology and metabolism	2015	PMID: 25695889
Germline and somatic SDHx alterations in apparently sporadic differentiated thyroid cancer.	Ni Y	Endocrine-related cancer	2015	PMID: 25694510
Germline PTEN, SDHB-D, and KLLN alterations in endometrial cancer patients with Cowden and Cowden-like syndromes: an international, multicenter, prospective study.	Mahdi H	Cancer	2015	PMID: 25376524
Disease variants in genomes of 44 centenarians.	Freudenberg-Hua Y	Molecular genetics & genomic medicine	2014	PMID: 25333069
Usefulness of Succinate dehydrogenase B (SDHB) immunohistochemistry in guiding mutational screening among patients with pheochromocytoma-paraganglioma syndromes.	Pai R	APMIS : acta pathologica, microbiologica, et immunologica Scandinavica	2014	PMID: 24735130
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327
A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma.	Rattenberry E	The Journal of clinical endocrinology and metabolism	2013	PMID: 23666964
An informatics approach to analyzing the incidentalome.	Berg JS	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22995991
Sequencing and analysis of a South Asian-Indian personal genome.	Gupta R	BMC genomics	2012	PMID: 22938532
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.	Johnston JJ	American journal of human genetics	2012	PMID: 22703879
Over-representation of the G12S polymorphism of the SDHD gene in patients with MEN2A syndrome.	Lendvai N	Clinics (Sao Paulo, Brazil)	2012	PMID: 22584711
Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53.	Ni Y	Human molecular genetics	2012	PMID: 21979946
A map of human genome variation from population-scale sequencing.	1000 Genomes Project Consortium	Nature	2010	PMID: 20981092
Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD.	Ricketts CJ	Human mutation	2010	PMID: 19802898
A role for succinate dehydrogenase genes in low chemoresponsiveness to hypoxia?	Richalet JP	Clinical autonomic research : official journal of the Clinical Autonomic Research Society	2009	PMID: 19768395
SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes.	Pasini B	Journal of internal medicine	2009	PMID: 19522823
Mutations and polymorphisms in the SDHB, SDHD, VHL, and RET genes in sporadic and familial pheochromocytomas.	Waldmann J	Endocrine	2009	PMID: 19399650
The first Dutch SDHB founder deletion in paraganglioma-pheochromocytoma patients.	Bayley JP	BMC medical genetics	2009	PMID: 19368708
Denaturing high performance liquid chromatography detection of SDHB, SDHD, and VHL germline mutations in pheochromocytoma.	Meyer-Rochow GY	The Journal of surgical research	2009	PMID: 19215943
Array-comparative genomic hybridization in sporadic benign pheochromocytomas.	van Nederveen FH	Endocrine-related cancer	2009	PMID: 19153209
Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes.	Ni Y	American journal of human genetics	2008	PMID: 18678321
High prevalence of SDHB mutations in head and neck paraganglioma in Belgium.	Persu A	Journal of hypertension	2008	PMID: 18551016
Intragenic mutations in thyroid cancer.	Sobrinho-Simões M	Endocrinology and metabolism clinics of North America	2008	PMID: 18502330
Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B (SDH-B) gene mutation carriers.	Srirangalingam U	Clinical endocrinology	2008	PMID: 18419787
Candidate gene mutation analysis in bilateral adrenal pheochromocytoma and sympathetic paraganglioma.	Korpershoek E	Endocrine-related cancer	2007	PMID: 17639058
Understanding and treating a channelopathy: severe myoclonic epilepsy of infancy.	Krauss GL	Neurology	2007	PMID: 17636058
Single nucleotide polymorphisms in succinate dehydrogenase subunits and citrate synthase genes: association results for impaired spermatogenesis.	Bonache S	International journal of andrology	2007	PMID: 17298551
Frequent genetic changes in childhood pheochromocytomas.	De Krijger RR	Annals of the New York Academy of Sciences	2006	PMID: 17102083
Genetic mutation screening in an italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients.	Castellano M	Annals of the New York Academy of Sciences	2006	PMID: 17102082
High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing.	Brouwers FM	The Journal of clinical endocrinology and metabolism	2006	PMID: 16912137
No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma.	Montani M	Endocrine-related cancer	2005	PMID: 16322339
Genetic and epigenetic profile of sporadic pheochromocytomas.	Cascon A	Journal of medical genetics	2004	PMID: 14985401
Hamosh, A. Personal Communication. 2018. Baltimore, Md.	-	-	-	-
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SDHB	-	-	-	-
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Text-mined citations for rs33927012 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 24, 2026