rs764575966

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PVS1_StrongPP5_Very_StrongBS2

The NM_003001.5(SDHC):c.397C>T(p.Arg133Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R133R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

SDHC
NM_003001.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 1.64

Variant links:

Genes affected

SDHC (HGNC:10682): (succinate dehydrogenase complex subunit C) This gene encodes one of four nuclear-encoded subunits that comprise succinate dehydrogenase, also known as mitochondrial complex II, a key enzyme complex of the tricarboxylic acid cycle and aerobic respiratory chains of mitochondria. The encoded protein is one of two integral membrane proteins that anchor other subunits of the complex, which form the catalytic core, to the inner mitochondrial membrane. There are several related pseudogenes for this gene on different chromosomes. Mutations in this gene have been associated with paragangliomas. Alternatively spliced transcript variants have been described. [provided by RefSeq, May 2013]

SDHC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.

PP5

Variant 1-161356832-C-T is Pathogenic according to our data. Variant chr1-161356832-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 183753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161356832-C-T is described in Lovd as [Pathogenic].

BS2

High AC in GnomAdExome at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHC	NM_003001.5 linkuse as main transcript	c.397C>T	p.Arg133Ter	stop_gained	5/6	ENST00000367975.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHC	ENST00000367975.7 linkuse as main transcript	c.397C>T	p.Arg133Ter	stop_gained	5/6	1	NM_003001.5	P1	Q99643-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

249038

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000539

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 31, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 04, 2018	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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	SDHC: PVS1:Strong, PM2, PP1:Moderate, PS4:Moderate -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This variant changes 1 nucleotide in exon 5 of the SDHC gene, creating a premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in over 20 individuals affected with hereditary paranganglioma-pheochromocytoma syndrome (PMID: 24758179, 25024072, 27700540, 28819017), and over 10 individuals with sporadic paranganglioma (PMID: 34750850). This variant is described as a common variant in the French Canadian population (PMID: 27700540), and it has been observed that this variant segregates with disease (PMID: 25024072, 27700540, 28819017). This variant has been identified in 10/280416 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of SDHC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 01, 2020	The p.Arg133X variant in SDHC is believed to be a French Canadian founder variant and been reported in >20 individuals, of mainly French Canadian and French ancestry, with paragangliomas/pheochromocytomas (PGL/PCC: Zbuk 2007, Burnichon 2009, Ricketts 2012, Lefevre 2014, Bickmann 2014, Shuch 2016, Bourdeau 2016). This variant segregated with PGL/PCC in at least 4 affected relatives from 2 families (Bourdeau 2016). In another family (Shuch 2016), the p.Arg133X variant segregated with both renal cell carcinoma (2 affected relatives) and PGL/PCC (1 affected relative). The p.Arg133X variant has also been identified in 0.009% (3/30782) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org; dbSNP rs764575966). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. This nonsense variant leads to a premature termination codon at position 133. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein that is missing ~22% of the coding region, with 37 amino acids removed. In summary, this variant meets criteria to be classified as pathogenic for hereditary paraganglioma-pheochromocytoma syndromes in an autosomal dominant manner based on its presence in multiple affected individuals, segregation studies, and low frequency in controls. ACMG/AMP criteria applied: PVS1_Strong, PS4, PM2, PP1_Moderate. -

Paragangliomas 3

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 08, 2024	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Gastrointestinal stromal tumor;C1847319:Carney-Stratakis syndrome;C1854336:Paragangliomas 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 19, 2021

- -

Gastrointestinal stromal tumor;C1854336:Paragangliomas 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

This sequence change creates a premature translational stop signal (p.Arg133*) in the SDHC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the SDHC protein. This variant is present in population databases (rs764575966, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with paragangliomas (PGLs) and gastrointestinal stromal tumor (PMID: 17898811, 23083876, 23282968, 24423348, 24523625, 24758179, 27700540). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183753). Studies have shown that this premature translational stop signal is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

Gastrointestinal stromal tumor

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 21, 2023

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2023

The p.R133* pathogenic mutation (also known as c.397C>T), located in coding exon 5 of the SDHC gene, results from a C to T substitution at nucleotide position 397. This changes the amino acid from an arginine to a stop codon within coding exon 5. This alteration occurs at the 3' terminus of SDHC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 37 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function. This alteration has been reported in multiple unrelated individuals with paragangliomas (PGLs), gastrointestinal stromal tumors (GIST), renal cell carcinomas, and an adrenocortical carcinoma (Ricketts CJ et al. J. Urol., 2012 Dec;188:2063-71; Miettinen M et al, 2013 Feb;37:234-40; Bickmann JK et al. J. Clin. Endocrinol. Metab., 2014 Mar;99:E489-96; Else T et al. J Clin Endocrinol Metab, 2014 Aug;99:E1482-6; Lefebvre M et al. Curr Oncol, 2014 Feb;21:e8-e17; Else T et al. Eur J Endocrinol, 2017 Nov;177:439-444). In addition, this alteration has been identified in multiple individuals with PGLs of French Canadian descent (Bourdeau I et al. J Clin Endocrinol Metab, 2016 12;101:4710-4718). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Carney-Stratakis syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 17, 2019

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.59

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Benign

0.75

MutationTaster

Benign

1.0

D;D;D;D;D

Vest4

0.98

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over