NM_003000.3(SDHB):c.689G>A (p.Arg230His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 24, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000131970.13

Allele description [Variation Report for NM_003000.3(SDHB):c.689G>A (p.Arg230His)]

NM_003000.3(SDHB):c.689G>A (p.Arg230His)

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.689G>A (p.Arg230His)

Other names:

p.R230H:CGC>CAC; p.Arg230His

HGVS:

NC_000001.11:g.17022684C>T
NG_012340.1:g.36487G>A
NM_003000.3:c.689G>AMANE SELECT
NP_002991.2:p.Arg230His
NP_002991.2:p.Arg230His
LRG_316t1:c.689G>A
LRG_316:g.36487G>A
LRG_316p1:p.Arg230His
NC_000001.10:g.17349179C>T
NM_003000.2:c.689G>A
p.R230H

Protein change:

R230H; ARG230HIS

Links:

OMIM: 185470.0023; dbSNP: rs587782604

NCBI 1000 Genomes Browser:

rs587782604

Molecular consequence:

NM_003000.3:c.689G>A - missense variant - [Sequence Ontology: SO:0001583]

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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Cutibacterium acnes TypeIA2 P.acn31, complete sequence
Cutibacterium acnes TypeIA2 P.acn31, complete sequence
gi|365961730|ref|NC_016511.1|

Nucleotide
F8QN77 (0)
Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000187028	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 24, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16314641, 19258401, 19454582, 20208144, 20592014, 20614293, 23083876, 27604842 Citation Link,
SCV000992188	Academic Department of Medical Genetics, University of Cambridge	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 26, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000187028

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 24, 2024)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV000992188

Academic Department of Medical Genetics, University of Cambridge

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 26, 2018)

germline

research

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Genetic testing in pheochromocytoma or functional paraganglioma.

Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP.

J Clin Oncol. 2005 Dec 1;23(34):8812-8.

PubMed [citation]

PMID:: 16314641

Genetics of pheochromocytoma and paraganglioma in Spanish patients.

Cascón A, Pita G, Burnichon N, Landa I, López-Jiménez E, Montero-Conde C, Leskelä S, Leandro-García LJ, Letón R, Rodríguez-Antona C, Díaz JA, López-Vidriero E, González-Neira A, Velasco A, Matias-Guiu X, Gimenez-Roqueplo AP, Robledo M.

J Clin Endocrinol Metab. 2009 May;94(5):1701-5. doi: 10.1210/jc.2008-2756. Epub 2009 Mar 3.

PubMed [citation]

PMID:: 19258401

See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV000187028.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The p.R230H pathogenic mutation (also known as c.689G>A), located in coding exon 7 of the SDHB gene, results from a G to A substitution at nucleotide position 689. The arginine at codon 230 is replaced by histidine, an amino acid with highly similar properties. In one study, this mutation was detected in a Mexican kindred in two relatives with head and neck paragangliomas whose tumors demonstrated loss of SDHB protein on immunohistochemistry (Cerecer-Gil et al. Clin Cancer Res 2010 Aug 15; 16(16):4148-54). An individual diagnosed with an autosomal recessive mitochondrial disease and leukoencephalopathy was found to be a compound heterozygote for SDHB p.D48V (c.143A>T) and SDHB p.R230H (c.689G>A) (Grønborg S et al. JIMD Rep. 2017 Sep;33:69-77). Furthermore, p.R230H has been reported in numerous additional kindreds with hereditary paraganglioma-pheochromocytoma, sporadic paraganglioma-pheochromocytoma, and familial renal cell carcinoma (Amar et al. J Clin Oncol. 2005 Dec1; 23(34):8812-8; Said-Al-Naief et al. Head Neck Pathol. 2008 Dec;2(4): 272-8; Ricketts CJ et al. J Urol. 2012; 188:2063-71; Cascón A et al. J Clin Endocrinol Metab. 2009; 94:1701-5; Burnichon N et al. J Clin Endocrinol Metab. 2009; 94:2817-27; Ma X et al. Front Endocrinol (Lausanne) 2020 Dec;11:574662). Two other pathogenic mutations (p.R230C and p.R230L) have also been described at this same codon. Based on available evidence, p.R230H is classified as a pathogenic mutation.

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

From Academic Department of Medical Genetics, University of Cambridge, SCV000992188.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (1)

Description

Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.

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

Last Updated: Sep 29, 2024

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