1-161340611-C-G

Position:

• chr1-161340611-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The ENST00000367975.7(SDHC):​c.197C>G​(p.Ala66Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A66V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHC ENST00000367975.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.775

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in ENST00000367975.7
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40618175).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHC	NM_003001.5	c.197C>G	p.Ala66Gly	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.197C>G	p.Ala66Gly	missense_variant	4/6	1	NM_003001.5	ENSP00000356953	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gastrointestinal stromal tumor;C1854336:Paragangliomas 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 22, 2018

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This sequence change replaces alanine with glycine at codon 66 of the SDHC protein (p.Ala66Gly). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SDHC-related disease. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

The p.A66G variant (also known as c.197C>G), located in coding exon 4 of the SDHC gene, results from a C to G substitution at nucleotide position 197. The alanine at codon 66 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;.;.;.;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.036	N
LIST_S2	Uncertain	0.93	D;D;D;D;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.41	T;T;T;T;T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.1	M;M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-2.6	D;D;N;N;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;T;D;D
Polyphen		0.072	B;D;B;B;P
Vest4		0.39
MutPred		0.72		Loss of stability (P = 0.0438);Loss of stability (P = 0.0438);.;.;.;
MVP		0.93
MPC		0.44
ClinPred		0.99	D
GERP RS		-4.8
Varity_R		0.37
gMVP		0.72

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: rs760572684; hg19: chr1-161310401;