rs587776653
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PM2PP3_StrongPP5_Moderate
The NM_003001.5(SDHC):c.405+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
SDHC
NM_003001.5 splice_donor
NM_003001.5 splice_donor
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 7.29
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 1-161356841-G-A is Pathogenic according to our data. Variant chr1-161356841-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7244.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-161356841-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SDHC | NM_003001.5 | c.405+1G>A | splice_donor_variant | ENST00000367975.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SDHC | ENST00000367975.7 | c.405+1G>A | splice_donor_variant | 1 | NM_003001.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Carney triad Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Section on Endocrinology and Genetics, National Institutes of Health / The Eunice Kennedy Shriver National Institute of Child Health and Human Development | - | - - |
Gastrointestinal stromal tumor;C1854336:Paragangliomas 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 20, 2019 | For these reasons, this variant has been classified as Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 17667967). Disruption of this splice site has been observed in individuals affected with paraganglioma and/or gastrointestinal stromal tumors (PMID: 17667967, 26173966, 24402737, 12658451, 21173220). ClinVar contains an entry for this variant (Variation ID: 7244). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in the last intron (intron 5) of the SDHC gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. - |
Gastrointestinal stromal tumor Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 04, 2011 | - - |
Hereditary pheochromocytoma-paraganglioma Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Section on Medical Neuroendocrinolgy, National Institutes of Health | - | - - |
Carney-Stratakis syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 04, 2011 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D;D;D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at