rs587776629
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_004589.4(SCO1):c.364_364+1delAG(p.Lys122fs) variant causes a frameshift, splice donor, splice region, intron change. The variant allele was found at a frequency of 0.000116 in 1,600,322 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
SCO1
NM_004589.4 frameshift, splice_donor, splice_region, intron
NM_004589.4 frameshift, splice_donor, splice_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.74
Genes affected
SCO1 (HGNC:10603): (synthesis of cytochrome C oxidase 1) Mammalian cytochrome c oxidase (COX) catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. In yeast, 2 related COX assembly genes, SCO1 and SCO2 (synthesis of cytochrome c oxidase), enable subunits 1 and 2 to be incorporated into the holoprotein. This gene is the human homolog to the yeast SCO1 gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-10695739-ACT-A is Pathogenic according to our data. Variant chr17-10695739-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 6177.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152066Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251236Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135814
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GnomAD4 exome AF: 0.000113 AC: 163AN: 1448256Hom.: 0 AF XY: 0.000108 AC XY: 78AN XY: 721702
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GnomAD4 genome AF: 0.000151 AC: 23AN: 152066Hom.: 0 Cov.: 32 AF XY: 0.000162 AC XY: 12AN XY: 74278
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 26, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 18, 2024 | Frameshift variant that results in protein truncation and unstable mRNA in a gene for which loss-of-function is a known mechanism of disease (PMID: 11013136); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11013136) - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 17, 2024 | This sequence change creates a premature translational stop signal (p.Lys122Valfs*28) in the SCO1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SCO1 are known to be pathogenic (PMID: 11013136, 23878101). This variant is present in population databases (rs745552237, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with cytochrome c oxidase deficiency and/or SCO1-related conditions (PMID: 11013136). It has also been observed to segregate with disease in related individuals. This variant is also known as c.364_364+1del, △GA; nt 363–364. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Mitochondrial complex 4 deficiency, nuclear type 4 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 18, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2000 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 4
DS_DL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at