rs587778661

Positions:

chr1-161328466-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

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 Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

SDHC
NM_003001.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:13U:1O: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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a chain Succinate dehydrogenase cytochrome b560 subunit, mitochondrial (size 139) in uniprot entity C560_HUMAN there are 17 pathogenic changes around while only 6 benign (74%) in NM_003001.5

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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135194.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=11, not_provided=1, Uncertain_significance=1, Pathogenic=2}. Variant chr1-161328466-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHC	NM_003001.5 linkuse as main transcript	c.148C>T	p.Arg50Cys	missense_variant	3/6	ENST00000367975.7	NP_002992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7 linkuse as main transcript	c.148C>T	p.Arg50Cys	missense_variant	3/6	1	NM_003001.5	ENSP00000356953	P1	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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:13Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2020	The SDHC c.148C>T; p.Arg50Cys variant (rs587778661) is reported in the literature in individuals affected with head and neck paraganglioma (Bennedbaek 2016, McInerney-Leo 2014, Neumann 2009, Rattenberry 2013). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 50 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.976). Additionally, a functional study of the orthologous variant in yeast suggests a mild effect on activity (Panizza 2013); however, it is unclear if this mild effect is clinically significant. Due to limited information, the clinical significance of the p.Arg50Cys variant is uncertain at this time. References: Bennedbaek M et al. Identification of eight novel SDHB, SDHC, SDHD germline variants in Danish pheochromocytoma/paraganglioma patients. Hered Cancer Clin Pract. 2016 Jun 8;14:13. 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;80(1):25-33. 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;69(8):3650-6. 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;22(4):804-15. 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;98(7):E1248-56. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2024	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Aug 23, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SDHC: PM2, PS3:Moderate, PS4:Moderate -

Paragangliomas 3

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Sep 05, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 17, 2023	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 08, 2024	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]. -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 09, 2018	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 05, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 18, 2024	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. -

Gastrointestinal stromal tumor;C1854336:Paragangliomas 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 30, 2023

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). 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 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

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 07, 2024

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 22, 2024

The c.148C>T (p.R50C) alteration is located in coding exon 3 of the SDHC gene. This alteration results from a C to T substitution at nucleotide position 148, causing the arginine (R) at amino acid position 50 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (1/152142) total alleles studied. The highest observed frequency was 0.001% (1/68030) of European (non-Finnish) alleles. This alteration has been detected in multiple individuals with a personal and/or family history that is consistent with SDHC-related disease (Neumann, 2009; Rattenberry, 2013; McInerney-Leo, 2014; Bennedbæk, 2016; Andrews, 2018; Casey, 2019; Main, 2020; Sen, 2020; Williams, 2022). Additionally, this alteration was identified in a minor diagnosed with acute promyelocytic leukemia (Byrjalsen, 2020). This amino acid position is highly conserved in available vertebrate species. In a yeast-based functional study, this alteration resulted in a significant reduction of SDH enzyme activity (Panizza, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

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

MutationTaster

Benign

1.0

D;D;D;D;D

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