chr1-161356815-A-G

Position:

chr1-161356815-A-G

Variant summary

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

The ENST00000367975.7(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
ENST00000367975.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 6.89

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in ENST00000367975.7

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-161356814-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 835716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 [Likely_pathogenic]. Clinvar id is 187084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-161356815-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHC	NM_003001.5 linkuse as main transcript	c.380A>G	p.His127Arg	missense_variant	5/6	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.380A>G	p.His127Arg	missense_variant	5/6	1	NM_003001.5	ENSP00000356953	P1	Q99643-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152132

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:

0.0000205

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727240

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:

0.0000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74312

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:

0.0000564

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Gastrointestinal stromal tumor

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	Dec 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 07, 2023	- -

Paragangliomas 3

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Dec 12, 2023	- -
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: 25494863, 24150194, 23666964]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Apr 02, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 10, 2020	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. -

Gastrointestinal stromal tumor;C1854336:Paragangliomas 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

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; Invitae). ClinVar contains an entry for this variant (Variation ID: 187084). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 03, 2022

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, 27011036, 33087929, 34703596, 34558728, 33237286, 24150194, 34308366, 34110302, 34301805) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;.;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

4.7

H;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.71

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

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.98

gMVP

0.99

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

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