chr1-161328466-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_003001.5(SDHC):c.148C>T(p.Arg50Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,612,542 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R50H) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

SDHC
NM_003001.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16O:1

Conservation

PhyloP100: 3.74

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 Pathogenic. Variant got 16 ACMG points.

PM1

In a topological_domain Mitochondrial matrix (size 32) in uniprot entity C560_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_003001.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-161328466-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3757977.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 1-161328466-C-T is Pathogenic according to our data. Variant chr1-161328466-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 135194.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161328466-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHC	NM_003001.5 link	c.148C>T	p.Arg50Cys	missense_variant	Exon 3 of 6	ENST00000367975.7	NP_002992.1	Q99643-1A0A0S2Z4B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7 link	c.148C>T	p.Arg50Cys	missense_variant	Exon 3 of 6	1	NM_003001.5	ENSP00000356953.3		Q99643-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

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

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1460400

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

726610

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74304

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

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000189

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Dec 04, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies in yeast demonstrate reduced SDH enzyme activity (PMID: 23175444); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23666964, 19351833, 24728327, 27279923, 25394176, 22517557, 31308404, 29386252, 20236688, 24102379, 33332384, 31567591, 31447099, 34558728, 32688340, 37019617, 26273102, 32035780, 30201732, 23175444) -

May 20, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHC c.148C>T (p.Arg50Cys) variant has been reported in the published literature in individuals affected with hereditary paraganglioma/pheochromocytoma syndrome (PMID: 34558728 (2022), 32688340 (2020), 32035780 (2020), 29386252 (2018), 27279923 (2016), 24102379 (2014), 23666964 (2013), 19351833 (2009)). Additionally, a functional study performed in a yeast model did not conclusively demonstrate a damaging effect of the orthologous variant on protein function (PMID: 23175444 (2013)). The frequency of this variant in the general population, 0.0000066 (1/152142 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 23, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 31, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHC c.148C>T; p.Arg50Cys variant (rs587778661, ClinVar Variation ID: 135194) is reported in the literature in multiple individuals affected with head and neck paraganglioma (Andrews 2018, Bennedbaek 2016, Haverfield 2021, Main 2020, McInerney-Leo 2014, Neumann 2009, Rattenberry 2013, Sen 2020, Williams 2022). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Functional analyses of the variant protein in yeast showed a reduction in enzyme activity (Panizza 2013). Computational analyses predict that this variant is deleterious (REVEL: 0.976). Based on available information, this variant is considered to be likely pathogenic. References: Andrews KA et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018 Jun. PMID: 29386252 Bennedbaek M et al. Identification of eight novel SDHB, SDHC, SDHD germline variants in Danish pheochromocytoma/paraganglioma patients. Hered Cancer Clin Pract. 2016 PMID: 27279923 Haverfield EV et al. Physician-directed genetic screening to evaluate personal risk for medically actionable disorders: a large multi-center cohort study. BMC Med. 2021 Aug 18. PMID: 34404389 Main AM et al. Genotype-phenotype associations in PPGLs in 59 patients with variants in SDHX genes. Endocr Connect. 2020 Aug. PMID: 32688340 McInerney-Leo AM et al. Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas. Clin Endocrinol (Oxf). 2014 Jan. PMID: 24102379 Neumann HP et al. Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res. 2009 Apr 15. PMID: 19351833 Panizza E et al. Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome. Hum Mol Genet. 2013 Feb 15. PMID: 23175444 Rattenberry E et al. A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2013 Jul. PMID: 23666964 Sen I et al. Tumor-specific prognosis of mutation-positive patients with head and neck paragangliomas. J Vasc Surg. 2020 May. PMID: 32035780 Williams ST et al. SDHC phaeochromocytoma and paraganglioma: A UK-wide case series. Clin Endocrinol (Oxf). 2022 Apr. PMID: 34558728 -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SDHC: PM2, PS3:Moderate, PS4:Moderate -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:4

Jul 18, 2024

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.148C>T (p.Arg50Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251468 control chromosomes. c.148C>T has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (Benn_2018, Bennedbaek_2016, Mclnerney-Leo_2014, Neumann_2009, Rattenberry_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The variant was shown to affect protein function (Panizza_2012). The following publications have been ascertained in the context of this evaluation (PMID: 30201732, 27279923, 24102379, 19351833, 23175444, 23666964). ClinVar contains an entry for this variant (Variation ID: 135194). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 24, 2025

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The following ACMG criteria have been used in classification: PM2_SUP (gnomAD 3.1.2, non-cancer); PP3; PS4_MOD; PS3_SUP; PP1. Observed in several healthy individuals, which may indicate reduced penetrance -

Sep 18, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 50 of the SDHC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in yeast have shown that this variant displays reduced succincate dehydrogenase activity and increased mtDNA mutability (PMID: 23175444). This variant has been reported in numerous individuals affected with paraganglioma and/pr pheochromocytoma (PMID: 19351833, 23666964, 24102379, 27279923, 29386252, 31308404, 32688340). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Feb 09, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg50Cys variant in SDHC has been reported in 4 individuals with hereditar y paraganglioma-pheochromocytoma syndrome (Neuman 2009, Rattenberry 2013, McIner ney-Leo 2014, Bennedbaek 2016), and segregated with the disease in 1 affected re lative (Bennedbaek 2016). It has also been reported by other clinical laboratori es in ClinVar (Variation ID 135194). The variant was absent from large populatio n studies, though it was identified in a reportedly healthy individual (<50yrs; Bodian 2014). In vitro functional studies provide some evidence that the p.Arg50 Cys variant may impact protein function in yeast (Panizza 2013) and computationa l prediction tools and conservation analysis suggest that the p.Arg50Cys variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Arg50Cys variant is likely pat hogenic. ACMG/AMP Criteria applied (Richards 2015): PM2; PS4_Moderate; PP3; PS3_ Supporting. -

Paragangliomas 3

Pathogenic:3

Sep 05, 2023

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This c.148C>T (p.Arg50Cys) variant in the SDHC gene has been reported in multiple unrelated patients with pheochromocytoma or paraganglioma (PMID: 19351833, 23666964, 24102379, 24728327, 27279923, 29386252, 31308404, 32688340) and segregated with the disease (PMID: 27279923). In addition, this variant was also identified in individuals with acute promyelocytic leukemia (PMID: 33332384). This variant is absent in the general population database. In vitro studies in the yeast showed that this variant significantly decreased succinate dehydrogenase activity (PMID: 23175444). Therefore, this c.148C>T (p.Arg50Cys) variant in the SDHC gene is classified as likely pathogenic. -

Feb 08, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 31308404, 27279923, 30201732]. This variant is expected to disrupt protein structure [Myriad internal data]. -

May 17, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Gastrointestinal stromal tumor;C1854336:Paragangliomas 3

Pathogenic:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 50 of the SDHC protein (p.Arg50Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pheochromocytoma or head and neck paranglioma (PMID: 19351833, 23666964, 24102379). ClinVar contains an entry for this variant (Variation ID: 135194). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SDHC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SDHC function (PMID: 23175444). For these reasons, this variant has been classified as Pathogenic. -

Gastrointestinal stromal tumor

Pathogenic:1

Feb 07, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Sep 25, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R50C variant (also known as c.148C>T), located in coding exon 3 of the SDHC gene, results from a C to T substitution at nucleotide position 148. The arginine at codon 50 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in multiple individuals with a personal and/or family history that is consistent with SDHC-related disease (Neumann HP et al. Cancer Res. 2009 Apr 15;69:3650-6; Rattenberry E et al. J. Clin. Endocrinol. Metab. 2013 Jul;98:E1248-56; McInerney-Leo AM et al. Clin. Endocrinol. (Oxf) 2014 Jan;80:25-33; Bennedbaek M et al. Hered. Cancer Clin. Pract. 2016 Jun;14:13; Andrews KA et al. J. Med. Genet., 2018 Jun;55:384-394; Casey RT et al. Sci Rep, 2019 07;9:10244; Main AM et al. Endocr Connect, 2020 Aug;9:793-803; Sen I et al. J Vasc Surg, 2020 May;71:1602-1612.e2; Williams ST et al. Clin Endocrinol (Oxf), 2022 Apr;96:499-512). Additionally, this alteration was identified in a minor diagnosed with acute promyelocytic leukemia (Byrjalsen A et al. PLoS Genet, 2020 12;16:e1009231). In a yeast-based functional study, this alteration resulted in a significant reduction of SDH enzyme activity (Panizza E et al. Hum. Mol. Genet. 2013 Feb;22:804-15). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified

Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

H;H

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-6.2

D;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.97

MVP

0.97

MPC

1.3

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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