1-161323636-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2

The NM_003001.5(SDHC):c.43C>T(p.Arg15*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,460 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. R15R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SDHC
NM_003001.5 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 2.15

Publications

26 publications found

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 Gene-Disease associations (from GenCC):

hereditary pheochromocytoma-paraganglioma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
pheochromocytoma/paraganglioma syndrome 3
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Carney-Stratakis syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
gastrointestinal stromal tumor
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
renal cell carcinoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
Cowden disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial disease
Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

SDHC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 62 pathogenic variants in the truncated region.

PP5

Variant 1-161323636-C-T is Pathogenic according to our data. Variant chr1-161323636-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 41776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 9 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHC	NM_003001.5 link	c.43C>T	p.Arg15*	stop_gained	Exon 2 of 6	ENST00000367975.7	NP_002992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7 link	c.43C>T	p.Arg15*	stop_gained	Exon 2 of 6	1	NM_003001.5	ENSP00000356953.3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152118

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000804

AC:

AN:

248902

AF XY:

0.00000742

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000616

AC:

AN:

1461342

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727004

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111584

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma

Pathogenic:6

Section on Medical Neuroendocrinolgy, National Institutes of Health

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Dec 11, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg15X variant in SDHC has been reported in at least 6 individuals with SDHC-associated cancers (Pasini 2008, Vandy 2011, Illouz 2012, Renella 2014, Else 2014). This variant has been identified in 0.003% (1/30594) South Asian chromosomes by chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 15, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the SDHC gene is an established disease mechanism in individuals with hereditary paragangliomas and pheochromocytomas. In summary, this variant meets criteria to be classified as pathogenic for hereditary paragangliomas and pheochromocytomas in an autosomal dominant manner. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. -

Jan 24, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The following ACMG criteria have been used in classification: PVS1; PS4_MOD -

Aug 28, 2023

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.43C>T (p.Arg15*) variant of the SDHC gene creates an early stop codon. It is expected to result in an absent or disrupted protein product. This variant has been reported in multiple individuals with paraganglioma, pheochromocytoma, gastrointestinal stromal tumors, and adrenocortical cancer (PMID: 17667967, 19351833, 21106325, 22868853, 24758179, 24781345, 27279923, 28412079). This variant has been identified in 2/248902 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss-of-function variants in SDHC are known to be pathogenic (PMID: 19546167, 17667967). Therefore, the c.43C>T (p.Arg15*) variant of the SDHC gene is classified as pathogenic. -

Oct 31, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant changes 1 nucleotide in exon 2 of the SDHC gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with phaeochromocytoma/paraganglioma (PMID: 19351833, 19454582, 21106325, 22868853, 24758179, 24781345, 28412079, 34558728). This variant has been identified in 2/248902 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. -

Feb 14, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SDHC c.43C>T (p.Arg15X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Paraganglioma-Pheochromocytoma in HGMD . The variant allele was found at a frequency of 8e-06 in 248902 control chromosomes (gnomAD). c.43C>T has been reported in the literature in multiple individuals affected with Paraganglioma-Pheochromocytoma (example: Williams_2021). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:3

Aug 17, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SDHC c.43C>T; p.Arg15Ter variant (rs201286421) is reported in the literature in multiple individuals affected with paraganglioma, gastrointestinal stromal tumors, or adrenocortical cancer (Else 2017, Illouz 2012, Pasini 2008, Renella 2014, Vandy 2011). This variant is found on only two chromosomes in the Genome Aggregation Database (2/248902 alleles), indicating it is not a common polymorphism. 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: Else T et al. Adrenocortical carcinoma and succinate dehydrogenase gene mutations: an observational case series. Eur J Endocrinol. 2017;177(5):439-444. Illouz F et al. Long-delayed localization of a cardiac functional paraganglioma with SDHC mutation. Ann Intern Med. 2012;157(3):222-223. Pasini B et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet. 2008;16(1):79-88. Renella R et al. Exploring the association of succinate dehydrogenase complex mutations with lymphoid malignancies. Fam Cancer. 2014;13(3):507-511. Vandy FC et al. Synchronous carotid body and thoracic paraganglioma associated with a germline SDHC mutation. J Vasc Surg. 2011;53(3):805-807. -

May 25, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19351833, 24781345, 24758179, 22517557, 27600092, 25525159, 19454582, 22703879, 22868853, 23934599, 17898811, 26269449, 26046366, 28412079, 28594934, 21106325, 29878124, 30050099, 28819017, 30301441, 27279923, 17667967, 32561571, 32741965, 30787465, 35668420, 34558728, 35731023, 33087929) -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pheochromocytoma/paraganglioma syndrome 3

Pathogenic:3

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2024

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Gastrointestinal stromal tumor;C1847319:Carney-Stratakis syndrome;C1854336:Pheochromocytoma/paraganglioma syndrome 3

Pathogenic:2

Apr 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PVS1+PS4 -

Gastrointestinal stromal tumor

Pathogenic:1

Mar 07, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SDHC-related disorder

Pathogenic:1

Jun 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SDHC c.43C>T variant is predicted to result in premature protein termination (p.Arg15*). This variant has been reported in multiple individuals with paraganglioma, pheochromocytoma, gastrointestinal stromal tumors, and adrenocortical cancer (Pasini et al. 2008. PubMed ID: 17667967; Vandy et al. 2010. PubMed ID: 21106325; Illouz et al. 2012. PubMed ID: 22868853; Renella et al. 2014. PubMed ID: 24781345; Else et al. 2017. PubMed ID: 28819017). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/41776/). Nonsense variants in SDHC are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Dec 13, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R15* pathogenic mutation (also known as c.43C>T), located in coding exon 2 of the SDHC gene, results from a C to T substitution at nucleotide position 43. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation has been observed in multiple individuals diagnosed with paragangliomas (PGL) (Pasini B et al. Eur J Hum Genet, 2008 Jan;16:79-88; Vandy FC et al. J. Vasc. Surg., 2011 Mar;53:805-7; llouz F et al. Ann. Intern. Med., 2012 Aug;157:222-3; Renella R et al. Fam. Cancer, 2014 Sep;13:507-11; Else T et al. J Clin Endocrinol Metab, 2014 Aug;99:E1482-6; Bennedbæk M et al. Hered Cancer Clin Pract, 2016 Jun;14:13; L'Huillier V et al. Eur Ann Otorhinolaryngol Head Neck Dis, 2017 Apr; Neumann HP et al. Cancer Res, 2009 Apr;69:3650-6; Smith JD et al. OTO Open Mar;5:2473974X21995453; Richter S et al. Genet Med, 2019 03;21:705-717; McCrary HC et al. JAMA Otolaryngol Head Neck Surg, 2019 07;145:641-646; Ong RKS et al. J Clin Endocrinol Metab, 2018 08;103:2802-2806). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Gastrointestinal stromal tumor;C1854336:Pheochromocytoma/paraganglioma syndrome 3

Pathogenic:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg15*) in the SDHC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHC are known to be pathogenic (PMID: 17667967, 19454582, 23282968, 24758179). This variant is present in population databases (rs201286421, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with paraganglioma, Hodgkin's lymphoma, pheochromocytoma, and/or gastrointestinal stromal tumors (PMID: 17667967, 19351833, 21106325, 22868853, 24781345). ClinVar contains an entry for this variant (Variation ID: 41776). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.85

PhyloP100

2.1

Vest4

0.93

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=2/198

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over