NM_003001.5(SDHC):c.397C>T (p.Arg133Ter) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Mar 1, 2023
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:: RCV000315495.28

Allele description [Variation Report for NM_003001.5(SDHC):c.397C>T (p.Arg133Ter)]

NM_003001.5(SDHC):c.397C>T (p.Arg133Ter)

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.397C>T (p.Arg133Ter)

HGVS:

NC_000001.11:g.161356832C>T
NG_012767.1:g.47457C>T
NM_001035511.3:c.242-5497C>T
NM_001035512.3:c.295C>T
NM_001035513.3:c.238C>T
NM_001278172.3:c.140-5497C>T
NM_001407115.1:c.517C>T
NM_001407116.1:c.340C>T
NM_001407117.1:c.334C>T
NM_001407118.1:c.289C>T
NM_001407119.1:c.286C>T
NM_001407120.1:c.286C>T
NM_001407121.1:c.185-5497C>T
NM_003001.5:c.397C>TMANE SELECT
NP_001030589.1:p.Arg99Ter
NP_001030590.1:p.Arg80Ter
NP_001394044.1:p.Arg173Ter
NP_001394045.1:p.Arg114Ter
NP_001394046.1:p.Arg112Ter
NP_001394047.1:p.Arg97Ter
NP_001394048.1:p.Arg96Ter
NP_001394049.1:p.Arg96Ter
NP_002992.1:p.Arg133Ter
NP_002992.1:p.Arg133Ter
LRG_317t1:c.397C>T
LRG_317:g.47457C>T
LRG_317p1:p.Arg133Ter
NC_000001.10:g.161326622C>T
NM_003001.3:c.397C>T
NR_103459.1:n.454C>T
NR_103459.3:n.449C>T
p.Arg133*
p.Arg133X
p.R133*

Protein change:

R112*

Links:

dbSNP: rs764575966

NCBI 1000 Genomes Browser:

rs764575966

Molecular consequence:

NM_001035511.3:c.242-5497C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001278172.3:c.140-5497C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001407121.1:c.185-5497C>T - intron variant - [Sequence Ontology: SO:0001627]
NR_103459.3:n.449C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_001035512.3:c.295C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001035513.3:c.238C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001407115.1:c.517C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001407116.1:c.340C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001407117.1:c.334C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001407118.1:c.289C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001407119.1:c.286C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001407120.1:c.286C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_003001.5:c.397C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000329512	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 4, 2022)	germline	clinical testing	Citation Link,
SCV000602179	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Apr 24, 2017)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 24423348, 24758179, 24523625, 19454582, 17898811, 23282968, 23083876, 27700540, 26467025
SCV000605081	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Mar 31, 2020)	germline	clinical testing	Citation Link,
SCV002064125	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 4, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003916530	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Mar 1, 2023)	germline	clinical testing	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
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Phenotypic variability and risk of malignancy in SDHC-linked paragangliomas: lessons from three unrelated cases with an identical germline mutation (p.Arg133*).

Bickmann JK, Sollfrank S, Schad A, Musholt TJ, Springer E, Miederer M, Bartsch O, Papaspyrou K, Koutsimpelas D, Mann WJ, Weber MM, Lackner KJ, Rossmann H, Fottner C.

J Clin Endocrinol Metab. 2014 Mar;99(3):E489-96. doi: 10.1210/jc.2013-3486. Epub 2014 Jan 1.

PubMed [citation]

PMID:: 24423348

The clinical phenotype of SDHC-associated hereditary paraganglioma syndrome (PGL3).

Else T, Marvin ML, Everett JN, Gruber SB, Arts HA, Stoffel EM, Auchus RJ, Raymond VM.

J Clin Endocrinol Metab. 2014 Aug;99(8):E1482-6. doi: 10.1210/jc.2013-3853. Epub 2014 Apr 23.

PubMed [citation]

PMID:: 24758179
PMCID:: PMC4121019

See all PubMed Citations (10)

Details of each submission

From GeneDx, SCV000329512.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 37 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22517557, 23282968, 26659639, 19351833, 28973655, 27634942, 24423348, 25525159, 17898811, 23083876, 19454582, 24523625, 24758179, 24102379, 25024072, 27493882, 27700540, 29339836, 26492543, 28819017, 29794110, 26490314, 29386252, 30201732, 31212687, 32272925, 33087929, 30787465, 31447099, 30877234)

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

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000602179.2

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

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000605081.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The SDHC c.397C>T, p.Arg133Ter variant (rs764575966) has been reported in multiple patients diagnosed with hereditary paraganglioma syndrome (Bickmann 2014, Zbuk 2007), renal cancer (Ricketts 2012) or gastrointestinal tumors (Miettinen 2013). It is reported as pathogenic in ClinVar (Variation ID: 183753), and observed in the general population with an allele frequency of 0.004% (10/280,416 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. REFERENCES Bickmann J et al. Phenotypic variability and risk of malignancy in SDHC-linked paragangliomas: lessons from three unrelated cases with an identical germline mutation (p.Arg133*). J Clin Endocrinol Metab. 2014; 99(3):E489-96. Miettinen M et al. Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. Am J Surg Pathol. 2013; 37(2):234-40. Ricketts C et al. Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. J Urol. 2012; 188(6):2063-71. Zbuk K et al. Germline mutations in PTEN and SDHC in a woman with epithelial thyroid cancer and carotid paraganglioma. Nat Clin Pract Oncol. 2007; 4(10):608-12.

#	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 Genetic Services Laboratory, University of Chicago, SCV002064125.1

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

Description

This sequence change results in the creation of a premature stop codon at amino acid position 133, p.Arg133*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated SDHC protein with potentially abnormal function. This pathogenic sequence change has previously been described in several patient with paragangliomas (OMIM# 605373; Bickmann et. al., 2014; Lefebvre et. al., 2014; Zbuk et. al., 2007). This variant was also found in the germline heterozygous state in several family members that were affected with renal cell carcinoma (Ricketts et. al., 2012). Our interpretation is based on the current understanding of the genetics of SDHC-related disorders.

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

From CeGaT Center for Human Genetics Tuebingen, SCV003916530.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

SDHC: PVS1:Strong, PM2, PP1:Moderate, PS4:Moderate

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

Last Updated: May 1, 2024

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