chr1-161340629-G-T

Position:

• chr1-161340629-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_003001.5(SDHC):​c.215G>T​(p.Arg72Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). 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)
• Consequence: SDHC NM_003001.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.31

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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, 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 chr1-161340628-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 653952.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=4, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 1-161340629-G-T is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHC	NM_003001.5	c.215G>T	p.Arg72Leu	missense_variant	4/6	ENST00000367975.7	NP_002992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7	c.215G>T	p.Arg72Leu	missense_variant	4/6	1	NM_003001.5	ENSP00000356953.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2020

The p.R72L pathogenic mutation (also known as c.215G>T), located in coding exon 4 of the SDHC gene, results from a G to T substitution at nucleotide position 215. The arginine at codon 72 is replaced by leucine, an amino acid with dissimilar properties. This mutation has been detected in an individual with a paraganglioma (Ambry internal data). Another alteration at the same codon, p.R72H (c.215G>A), has been described in multiple individuals with a paraganglioma (Burnichon N et al. J Clin Endocrinol Metab, 2009 Aug;94:2817-27; Buffet A et al. Horm Metab Res, 2012 May;44:359-66; Gupta S et al. Endocr Pathol, 2016 Sep;27:243-52). Based on internal structural analysis, p.R72L disrupts the catalytic function of succinate dehydrogenase, via 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). 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	0.95
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.2	D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		1.0	D;P;D;D;D
Vest4		0.94
MutPred		0.89		Loss of methylation at R72 (P = 0.0149);Loss of methylation at R72 (P = 0.0149);.;.;.;
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.94
gMVP		0.97

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

Other links and lift over

dbSNP: rs778582853; hg19: chr1-161310419;