NM_003000.3(SDHB):c.574T>C (p.Cys192Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 19, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000165688.5

Allele description [Variation Report for NM_003000.3(SDHB):c.574T>C (p.Cys192Arg)]

NM_003000.3(SDHB):c.574T>C (p.Cys192Arg)

Gene:

SDHB:succinate dehydrogenase complex iron sulfur subunit B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.13

Genomic location:

Preferred name:

NM_003000.3(SDHB):c.574T>C (p.Cys192Arg)

HGVS:

NC_000001.11:g.17024041A>G
NG_012340.1:g.35130T>C
NM_003000.3:c.574T>CMANE SELECT
NP_002991.2:p.Cys192Arg
NP_002991.2:p.Cys192Arg
LRG_316t1:c.574T>C
LRG_316:g.35130T>C
LRG_316p1:p.Cys192Arg
NC_000001.10:g.17350536A>G
NM_003000.2:c.574T>C
P21912:p.Cys192Arg
p.C192R

Protein change:

C192R

Links:

UniProtKB: P21912#VAR_035066; dbSNP: rs786202732

NCBI 1000 Genomes Browser:

rs786202732

Molecular consequence:

NM_003000.3:c.574T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000216426	Ambry Genetics	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022)	Pathogenic (May 19, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 12000816, 17200167, 18382370, 19454582, 22517554, 22835832, 22904323, 27785149, 28503760 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000216426

Ambry Genetics

criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)

Pathogenic
(May 19, 2022)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Germ-line mutations in nonsyndromic pheochromocytoma.

Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, et al.

N Engl J Med. 2002 May 9;346(19):1459-66.

PubMed [citation]

PMID:: 12000816

Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas.

Timmers HJ, Kozupa A, Eisenhofer G, Raygada M, Adams KT, Solis D, Lenders JW, Pacak K.

J Clin Endocrinol Metab. 2007 Mar;92(3):779-86. Epub 2007 Jan 2.

PubMed [citation]

PMID:: 17200167

See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV000216426.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

Description

The p.C192R pathogenic mutation (also known as c.574T>C), located in coding exon 6 of the SDHB gene, results from a T to C substitution at nucleotide position 574. The cysteine at codon 192 is replaced by arginine, an amino acid with highly dissimilar properties.This alteration has been identified in numerous individuals with paragangliomas and pheochromocytomas (Neumann HP et al. N. Engl. J. Med. 2002 May;346(19):1459-66; Lefebvre S et al. Horm. Metab. Res. 2012 May;44(5):334-8; Burnichon N et al. J. Clin. Endocrinol. Metab. 2009 Aug;94(8):2817-27; Klein RD et al. Diagn. Mol. Pathol. 2008 Jun;17(2):94-100; Timmers HJ et al. J. Clin. Endocrinol. Metab. 2007 Mar; 92(3):779-86; Michaowska I et al. Kardiochir Torakochirurgia Pol, 2016 Sep;13:276-282). In one series of functional studies, the SDHB p.C192R mutant protein was subject to premature degradation, possibly due to the increased ubiquitination levels observed in the mutant protein compared to wild type SDHB protein (Yang C et al. FASEB J. 2012 Nov;26(11):4506-16). The Cys192 residue plays a vital role coordinating the Fe4S4 cluster and it is believed that alterations at this location would prevent assembly of Complex II (Iverson TM et al. J. Biol. Chem. 2012 Oct;287(42):35430-8). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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