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

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 15, 2023
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:: RCV001058694.5

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:: Gastrointestinal stromal tumor
Synonyms:: Gastrointestinal Stromal Sarcoma; Gastrointestinal stromal tumor, somatic; Gastrointestinal stroma tumor
Identifiers:: MONDO: MONDO:0011719; MeSH: D046152; MedGen: C0238198; Orphanet: 44890; OMIM: 606764; Human Phenotype Ontology: HP:0100723

Name:: Paragangliomas 4 (PPGL4)
Synonyms:: CAROTID BODY TUMORS AND MULTIPLE EXTRAADRENAL PHEOCHROMOCYTOMAS; Pheochromocytoma, extraadrenal and cervical paraganglioma; Paragangliomas, hereditary extraadrenal; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007273; MedGen: C1861848; Orphanet: 29072; OMIM: 115310

Name:: Pheochromocytoma
Synonyms:: Chromaffinoma; Chromaffin paraganglioma; Chromaffin tumor; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008233; MedGen: C0031511; Orphanet: 29072; OMIM: 171300; Human Phenotype Ontology: HP:0002666

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001223283	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 15, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 18551016, 34906457, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001223283

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 15, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

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

Quantifying evidence toward pathogenicity for rare phenotypes: The case of succinate dehydrogenase genes, SDHB and SDHD.

Garrett A, Loveday C, King L, Butler S, Robinson R, Horton C, Yussuf A, Choi S, Torr B, Durkie M, Burghel GJ, Drummond J, Berry I, Wallace A, Callaway A, Eccles D, Tischkowitz M, Tatton-Brown K, Snape K, McVeigh T, Izatt L, Woodward ER, et al.

Genet Med. 2022 Jan;24(1):41-50. doi: 10.1016/j.gim.2021.08.004. Epub 2021 Nov 30.

PubMed [citation]

PMID:: 34906457
PMCID:: PMC8759765

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001223283.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 248 of the SDHB protein (p.Asn248Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paraganglioma (PMID: 18551016, 34906457; Invitae). ClinVar contains an entry for this variant (Variation ID: 428929). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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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