NM_003000.3(SDHB):c.744C>G (p.Asn248Lys) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 31, 2021
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:: RCV000492396.4

Allele description [Variation Report for NM_003000.3(SDHB):c.744C>G (p.Asn248Lys)]

NM_003000.3(SDHB):c.744C>G (p.Asn248Lys)

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.744C>G (p.Asn248Lys)

HGVS:

NC_000001.11:g.17022629G>C
NG_012340.1:g.36542C>G
NM_003000.3:c.744C>GMANE SELECT
NP_002991.2:p.Asn248Lys
NP_002991.2:p.Asn248Lys
LRG_316t1:c.744C>G
LRG_316:g.36542C>G
LRG_316p1:p.Asn248Lys
NC_000001.10:g.17349124G>C
NM_003000.2:c.744C>G

Protein change:

N248K

Links:

dbSNP: rs1131691058

NCBI 1000 Genomes Browser:

rs1131691058

Molecular consequence:

NM_003000.3:c.744C>G - 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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000581209	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Dec 31, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15989954, 18551016, 23512077, 24758379, 25720320 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000581209

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Dec 31, 2021)

germline

clinical testing

PubMed (5)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Crystal structure of mitochondrial respiratory membrane protein complex II.

Sun F, Huo X, Zhai Y, Wang A, Xu J, Su D, Bartlam M, Rao Z.

Cell. 2005 Jul 1;121(7):1043-57.

PubMed [citation]

PMID:: 15989954

High prevalence of SDHB mutations in head and neck paraganglioma in Belgium.

Persu A, Hamoir M, Grégoire V, Garin P, Duvivier E, Reychler H, Chantrain G, Mortier G, Mourad M, Maiter D, Vikkula M.

J Hypertens. 2008 Jul;26(7):1395-401. doi: 10.1097/HJH.0b013e3282ffdc54.

PubMed [citation]

PMID:: 18551016

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000581209.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.N248K variant (also known as c.744C>G), located in coding exon 7 of the SDHB gene, results from a C to G substitution at nucleotide position 744. The asparagine at codon 248 is replaced by lysine, an amino acid with similar properties. This alteration has been previously described in multiple individuals diagnosed with paragangliomas and/or pheochromocytomas (Persu A et al. J. Hypertens., 2008 Jul;26:1395-401; Fishbein L et al. Ann Surg Oncol, 2013 May;20:1444-50; Papathomas TG et al. Mod. Pathol., 2015 Jun;28:807-21). Based on internal structural assessment, this variant introduces a positive charge near the quinone-reducing active site and affects the final electron transfer reaction (Sun F et al. Cell, 2005 Jul;121:1043-57; Liu J et al. Chem. Rev., 2014 Apr;114:4366-469). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	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

Last Updated: Sep 29, 2024

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