rs786203457

Variant names:

• chr1-161356815-A-G
• rs786203457
• NM_003001.5:c.380A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 16P and 4B. PM1 PM5 PP3_Strong PP5_Very_Strong BS2

The NM_003001.5(SDHC):​c.380A>G​(p.His127Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,614,010 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. H127D) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: SDHC NM_003001.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 6.89
• Publications: 18 publications found

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

ACMG classification

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

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 34 uncertain in NM_003001.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-161356814-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1677290.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 1-161356815-A-G is Pathogenic according to our data. Variant chr1-161356815-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 187084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 30 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHC	NM_003001.5	c.380A>G	p.His127Arg	missense_variant	Exon 5 of 6	ENST00000367975.7	NP_002992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7	c.380A>G	p.His127Arg	missense_variant	Exon 5 of 6	1	NM_003001.5	ENSP00000356953.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32

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: 0.0000205 AC: 30 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74312

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00000899 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Mar 30, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23162105, 29386252, 25025441, 31579262, 19332149, 23666964, 26259135, 25494863, 23282968, 25394176, 24886695, 26273102, 23833252, 24625421, 24096523, 33087929, 34703596, 34558728, 34308366, 34110302, 34301805, 24150194, 35739278, 36195768, 36449569, 28873162, 31308404, 27011036) -

Jun 03, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SDHC c.380A>G (p.His127Arg) variant has been reported in the published literature in individuals with pheochromocytoma and paraganglioma (PGL-PCC) (PMID: 23666964 (2013), 25494863 (2015), 29386252 (2018), 30201732 (2018), 32751108 (2020), 34110302 (2021), 36045543 (2022)). This variant has also been reported in individuals with gastrointestinal stromal tumor (GIST) (PMID: 31308404 (2019), 32751108 (2020), 34308366 (2021), 36198483 (2023)), renal carcinoma (PMID: 25025441 (2014), 32751108 (2020)), pituitary adenoma (PMID: 24625421 (2014), 36449569 (2023)) and acute lymphoblastic leukemia (ALL) (PMID: 35739278 (2022)). The frequency of this variant in the general population, 0.000032 (1/31390 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 pathogenic. -

Gastrointestinal stromal tumor Pathogenic:2

Dec 15, 2020

Department of Pediatrics, Memorial Sloan Kettering Cancer Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Dec 07, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pheochromocytoma/paraganglioma syndrome 3 Pathogenic:2

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: 25494863, 24150194, 23666964]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Dec 12, 2023

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary pheochromocytoma-paraganglioma Pathogenic:2

Apr 02, 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 histidine with arginine at codon 127 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). To our knowledge, functional studies have not been reported for this variant, however histidine-127 is a key amino acid for heme binding (PMID: 15989954) and mutations of this residue abolish SDHC protein levels, destabilize of SDHD and SDHB level, and abrogate both succinate ubiquinone oxidoreductase (SQR) and succinate dehydrogenase (SDH) (complex II) enzymatic activities in mitochondria (PMID: 19332149). This variant has been reported in individuals affected with paragangliomas, gastrointestinal stromal tumors (GIST), renal cell carcinoma, and pituitary adenomas (PMID: 23282968, 23666964, 24150194, 24625421, 25025441, 25494863, 29386252, 31308404, 34110302, 34558728). This variant has been identified in 1/31390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Aug 10, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.His127Arg variant in SDHC has been reported in 6 individuals with SDHC-related tumors and segregated with disease in 1 affected individual from 1 family (Gill 2013 PMID: 24150194; Miettinen 2013 PMID: 23282968; Denes 2015 PMID: 25494863; Rattenberry 2013 PMID: 23666964; Casey 2019 PMID 31308404; Invitae). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 187084). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant SDHC-related tumors. ACMG/AMP Criteria applied: PM2, PP3, PS4_Strong. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 29, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H127R pathogenic mutation (also known as c.380A>G), located in coding exon 5 of the SDHC gene, results from an A to G substitution at nucleotide position 380. The histidine at codon 127 is replaced by arginine, an amino acid with highly similar properties. The mutation has been detected in multiple individuals with paraganglioma(s) (Rattenberry E et al. J Clin Endocrinol Metab, 2013 Jul;98:E1248-56; Dénes J et al. J Clin Endocrinol Metab, 2015 Mar;100:E531-41; Andrews KA et al. J Med Genet, 2018 06;55:384-394; Ambry internal data). It has also been identified in patients with a succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor and/or renal carcinoma (Gill AJ et al. Pathology, 2013 12;45:689-91; Gill AJ et al. Am J Surg Pathol, 2014 Dec;38:1588-602; Casey RT et al. Sci Rep, 2019 07;9:10244; Ambry internal data). Based on internal structural analysis, this mutation disrupts the SDHC heme-binding site, within which there are other internally pathogenic variants (Sun F et al. Cell, 2005 Jul;121:1043-57; Fufezan C et al. Proteins, 2008 Nov;73:690-704; Lemarie A et al. Mitochondrion, 2009 Jul;9:254-60). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Gastrointestinal stromal tumor;C1854336:Pheochromocytoma/paraganglioma syndrome 3 Pathogenic:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 127 of the SDHC protein (p.His127Arg). This variant is present in population databases (rs786203457, gnomAD no frequency). This missense change has been observed in individuals with gastrointestinal stromal tumor, renal carcinoma and papillary thyroid carcinoma and paraganglioma (PMID: 23666964, 24150194, 25494863; internal data). ClinVar contains an entry for this variant (Variation ID: 187084). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). This variant disrupts the p.His127 amino acid residue in SDHC. Other variant(s) that disrupt this residue have been observed in individuals with SDHC-related conditions (PMID: 22517557, 24758179), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Pathogenic	4.7	H;.;.
PhyloP100		6.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-7.5	D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.98
MutPred		0.94		Gain of MoRF binding (P = 0.0146);.;.;
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.98
gMVP		0.99
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786203457; hg19: chr1-161326605;