chr1-161328478-C-T

Variant names:

• chr1-161328478-C-T
• NM_003001.5:c.160C>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_003001.5(SDHC):​c.160C>T​(p.Pro54Ser) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P54T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHC NM_003001.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 5.52

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a topological_domain Mitochondrial matrix (size 32) in uniprot entity C560_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) 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 chr1-161328478-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465962.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 1-161328478-C-T is Pathogenic according to our data. Variant chr1-161328478-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1776361.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHC	NM_003001.5	c.160C>T	p.Pro54Ser	missense_variant	Exon 3 of 6	ENST00000367975.7	NP_002992.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHC	ENST00000367975.7	c.160C>T	p.Pro54Ser	missense_variant	Exon 3 of 6	1	NM_003001.5	ENSP00000356953.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 14, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P54S variant (also known as c.160C>T), located in coding exon 3 of the SDHC gene, results from a C to T substitution at nucleotide position 160. The proline at codon 54 is replaced by serine, an amino acid with similar properties. This variant has been identified in an individual with recurrent paragangliomas and gastrointestinal stromal tumor (Ambry internal data). Another alteration at the same codon, p.P54T (c.160C>A), has been detected in multiple individuals with paragangliomas (Ambry internal data). Based on internal structural analysis, P54S destabilizes the SDHC-SDHB interface to a higher degree than a nearby pathogenic variant (Zhou Q et al. Protein Cell, 2011 Jul;2:531-42; Inaoka DK et al. Int J Mol Sci, 2015 Jul;16:15287-308). This variant was not reported in population-based 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Gastrointestinal stromal tumor;C1854336:Paragangliomas 3 Uncertain:1

May 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 disruptive. ClinVar contains an entry for this variant (Variation ID: 1776361). This variant has not been reported in the literature in individuals affected with SDHC-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 54 of the SDHC protein (p.Pro54Ser). This variant disrupts the p.Pro54 amino acid residue in SDHC. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae; external communication). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Hereditary pheochromocytoma-paraganglioma Uncertain:1

Feb 24, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces proline with serine at codon 54 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. This variant has not been reported in individuals affected with SDHC-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.6	H;H
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.86		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-161298268;