NM_003001.5(SDHC):c.224G>A (p.Gly75Asp) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 25, 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:: RCV000688261.6

Allele description [Variation Report for NM_003001.5(SDHC):c.224G>A (p.Gly75Asp)]

NM_003001.5(SDHC):c.224G>A (p.Gly75Asp)

Gene:

SDHC:succinate dehydrogenase complex subunit C [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q23.3

Genomic location:

Preferred name:

NM_003001.5(SDHC):c.224G>A (p.Gly75Asp)

HGVS:

NC_000001.11:g.161340638G>A
NG_012767.1:g.31263G>A
NM_001035511.3:c.224G>A
NM_001035512.3:c.122G>A
NM_001035513.3:c.65G>A
NM_001278172.3:c.122G>A
NM_001407115.1:c.344G>A
NM_001407116.1:c.167G>A
NM_001407117.1:c.167G>A
NM_001407118.1:c.122G>A
NM_001407119.1:c.113G>A
NM_001407120.1:c.113G>A
NM_001407121.1:c.167G>A
NM_003001.5:c.224G>AMANE SELECT
NP_001030588.1:p.Gly75Asp
NP_001030588.1:p.Gly75Asp
NP_001030589.1:p.Gly41Asp
NP_001030589.1:p.Gly41Asp
NP_001030590.1:p.Gly22Asp
NP_001030590.1:p.Gly22Asp
NP_001265101.1:p.Gly41Asp
NP_001265101.1:p.Gly41Asp
NP_001394044.1:p.Gly115Asp
NP_001394045.1:p.Gly56Asp
NP_001394046.1:p.Gly56Asp
NP_001394047.1:p.Gly41Asp
NP_001394048.1:p.Gly38Asp
NP_001394049.1:p.Gly38Asp
NP_001394050.1:p.Gly56Asp
NP_002992.1:p.Gly75Asp
NP_002992.1:p.Gly75Asp
LRG_317t1:c.224G>A
LRG_317:g.31263G>A
LRG_317p1:p.Gly75Asp
NC_000001.10:g.161310428G>A
NM_001035511.2:c.224G>A
NM_001035512.2:c.122G>A
NM_001035513.2:c.65G>A
NM_001278172.2:c.122G>A
NM_003001.3:c.224G>A
NR_103459.2:n.276G>A
NR_103459.3:n.276G>A

Protein change:

G115D

Links:

dbSNP: rs786205147

NCBI 1000 Genomes Browser:

rs786205147

Molecular consequence:

NM_001035511.3:c.224G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001035512.3:c.122G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001035513.3:c.65G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001278172.3:c.122G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407115.1:c.344G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407116.1:c.167G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407117.1:c.167G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407118.1:c.122G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407119.1:c.113G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407120.1:c.113G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001407121.1:c.167G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003001.5:c.224G>A - 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 3 (PPGL3)
Synonyms:: Glomus tumors, familial, 3; SDHC-Related Hereditary Paraganglioma-Pheochromocytoma Syndrome (Paragangliomas 3); PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 3
Identifiers:: MONDO: MONDO:0011544; MedGen: C1854336; Orphanet: 29072; OMIM: 605373

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000815866	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 25, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19351833, 26173966, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000815866

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 25, 2021)

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

Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out.

Neumann HP, Erlic Z, Boedeker CC, Rybicki LA, Robledo M, Hermsen M, Schiavi F, Falcioni M, Kwok P, Bauters C, Lampe K, Fischer M, Edelman E, Benn DE, Robinson BG, Wiegand S, Rasp G, Stuck BA, Hoffmann MM, Sullivan M, Sevilla MA, Weiss MM, et al.

Cancer Res. 2009 Apr 15;69(8):3650-6. doi: 10.1158/0008-5472.CAN-08-4057. Epub 2009 Apr 7.

PubMed [citation]

PMID:: 19351833

Carney triad can be (rarely) associated with germline succinate dehydrogenase defects.

Boikos SA, Xekouki P, Fumagalli E, Faucz FR, Raygada M, Szarek E, Ball E, Kim SY, Miettinen M, Helman LJ, Carney JA, Pacak K, Stratakis CA.

Eur J Hum Genet. 2016 Apr;24(4):569-73. doi: 10.1038/ejhg.2015.142. Epub 2015 Jul 15.

PubMed [citation]

PMID:: 26173966
PMCID:: PMC4929866

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000815866.3

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

Description

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. 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 SDHC protein function. ClinVar contains an entry for this variant (Variation ID: 189841). This missense change has been observed in individuals with paraganglioma and condroma (PMID: 19351833, 26173966; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 75 of the SDHC protein (p.Gly75Asp).

#	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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