rs1060501387

Positions:

• chr1-161356809-T-C
• chr1-161356809-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_003001.5(SDHC):​c.374T>C​(p.Met125Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict 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. M125R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SDHC NM_003001.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.403

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 Likely_pathogenic. Variant got 6 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, 13 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 chr1-161356809-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 407057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHC	NM_003001.5	c.374T>C	p.Met125Thr	missense_variant	5/6	ENST00000367975.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHC	ENST00000367975.7	c.374T>C	p.Met125Thr	missense_variant	5/6	1	NM_003001.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727240

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gastrointestinal stromal tumor;C1854336:Paragangliomas 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 28, 2023

This variant is not present in population databases (gnomAD no frequency). 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 output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 407048). This variant has not been reported in the literature in individuals affected with SDHC-related conditions. This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 125 of the SDHC protein (p.Met125Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	13
DANN	Benign	0.78
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.43	N;.;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.36	N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.73	T;T;T
Polyphen		0.0070	B;B;B
Vest4		0.56
MutPred		0.70		Gain of catalytic residue at M125 (P = 0.0073);.;.;
MVP		0.81
MPC		0.42
ClinPred		0.19	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.057
gMVP		0.62

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: rs1060501387; hg19: chr1-161326599;