rs778582853

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_003001.5(SDHC):c.215G>A(p.Arg72His) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,644 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. R72C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SDHC
NM_003001.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 4.31

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 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 0 benign, 15 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 chr1-161340629-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 480787.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

PP5

Variant 1-161340629-G-A is Pathogenic according to our data. Variant chr1-161340629-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407044.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1, Pathogenic=1}. Variant chr1-161340629-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHC	NM_003001.5 linkuse as main transcript	c.215G>A	p.Arg72His	missense_variant	4/6	ENST00000367975.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHC	ENST00000367975.7 linkuse as main transcript	c.215G>A	p.Arg72His	missense_variant	4/6	1	NM_003001.5	P1	Q99643-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

248980

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134780

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461644

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 27, 2021

Not observed at a significant frequency in large population cohorts (Lek 2016); 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: 33676450, 28196207, 22517557, 27262318, 19454582) -

Gastrointestinal stromal tumor

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 31, 2022

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2023

The p.R72H pathogenic mutation (also known as c.215G>A), located in coding exon 4 of the SDHC gene, results from a G to A substitution at nucleotide position 215. The arginine at codon 72 is replaced by histidine, an amino acid with highly similar properties. In a prospective series of individuals with paragangliomas, this alteration was identified in five individuals from three families (Burnichon N et al. J Clin Endocrinol Metab, 2009 Aug;94:2817-27). In addition, this alteration was identified in a French cohort of 1640 index patients with PGL/PCC (Buffet A et al. Horm Metab Res, 2012 May;44:359-66). This alteration has also been observed in an individual with urinary bladder paraganglioma whose tumor demonstrated loss of SDHB expression on IHC (Gupta S et al. Endocr Pathol, 2016 Sep;27:243-52). Based on internal structural analysis, p.R72H disrupts the catalytic function of succinate dehydrogenase through impacts on quinone binding and/or reduction to quinol (Sun F et al. Cell, 2005 Jul;121:1043-57; Lemarie A et al. Mitochondrion, 2009 Jul;9:254-60; Kluckova K et al. Cell Death Dis, 2015 May;6:e1749). 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. -

Hereditary pheochromocytoma-paraganglioma

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jun 26, 2023

This missense variant replaces arginine with histidine at codon 72 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 another variant at this residue (p.Arg72Cys) has been shown to have reduced electron transfer to ubiquinone and decreased succinate dehydrogenase activity (PMID: 25950479). This variant has been reported in multiple individuals affected with hereditary paranganglioma-pheochromocytoma syndrome (PMID: 19454582, 22517557, 27262318). Other variants at this protein residue (p.Arg72Cys, p.Arg72Leu) have been classified as pathogenic in ClinVar indicating that this residue is disease causing (ClinVar Variation IDs: 653952, 480787). This variant has been identified in 2/248980 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Gastrointestinal stromal tumor;C1854336:Paragangliomas 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 72 of the SDHC protein (p.Arg72His). This variant is present in population databases (rs778582853, gnomAD 0.006%). This missense change has been observed in individual(s) with head and neck and/or thoracic-abdominal, pelvic, or urinary bladder paraganglioma (PMID: 19454582, 27262318). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 407044). 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

D;.;.;.;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

D;T;T;D;T

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.94

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.7

H;H;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.3

D;D;D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.014

D;D;D;D;T

Sift4G

Uncertain

0.013

D;T;D;D;T

Polyphen

1.0

D;P;D;D;D

Vest4

0.95

MutPred

0.88

Loss of methylation at R72 (P = 0.0149);Loss of methylation at R72 (P = 0.0149);.;.;.;

MVP

0.99

MPC

0.72

ClinPred

1.0

GERP RS

4.1

Varity_R

0.80

gMVP

0.94

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