rs1553262444

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_003001.5(SDHC):c.160C>A(p.Pro54Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,232 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P54S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SDHC
NM_003001.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 5.52

Publications

0 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 11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 37 uncertain in NM_003001.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-161328478-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1776361.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.995

PP5

Variant 1-161328478-C-A is Pathogenic according to our data. Variant chr1-161328478-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465962.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHC	NM_003001.5 link	c.160C>A	p.Pro54Thr	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.160C>A	p.Pro54Thr	missense_variant	Exon 3 of 6	1	NM_003001.5	ENSP00000356953.3		Q99643-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456232

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724926

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33366

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26106

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1106888

Other (OTH)

AF:

0.00

AC:

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:1

Apr 09, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P54T variant (also known as c.160C>A), located in coding exon 3 of the SDHC gene, results from a C to A substitution at nucleotide position 160. The proline at codon 54 is replaced by threonine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with hereditary pheochromocytoma-paraganglioma (Ambry internal data; external communication). Based on internal structural analysis, this alteration destabilizes the SDHC-SDHB interface to a higher degree than a nearby pathogenic variant (Zhou Q et al. Protein Cell, 2011 Jul;2:531-42; Inaoka DK et al. Int J Mol Sci, 2015 Jul;16:15287-308). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Gastrointestinal stromal tumor;C1854336:Pheochromocytoma/paraganglioma syndrome 3

Pathogenic:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 54 of the SDHC protein (p.Pro54Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with gastrointestinal stromal tumors and/or paragangliomas (external communication, internal data). ClinVar contains an entry for this variant (Variation ID: 465962). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided

Uncertain:1

Jun 29, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with an SDH-deficient gastrointestinal stromal tumor (Boikos 2016); This variant is associated with the following publications: (PMID: 27011036) -

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

Uncertain:1

May 03, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary pheochromocytoma-paraganglioma

Uncertain:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.6

H;H

PhyloP100

5.5

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.2

D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0050

D;D

Polyphen

1.0

D;D

Vest4

0.95

MutPred

0.87

Gain of catalytic residue at P54 (P = 0.0635);Gain of catalytic residue at P54 (P = 0.0635);

MVP

0.97

MPC

1.2

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.97

Mutation Taster

=15/85

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over