1-244842061-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_198076.6(COX20):​c.157+3G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000876 in 1,587,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00090 ( 0 hom. )

Consequence

COX20
NM_198076.6 splice_region, intron

Scores

2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:3

Conservation

PhyloP100: 1.62
Variant links:
Genes affected
COX20 (HGNC:26970): (cytochrome c oxidase assembly factor COX20) This gene encodes a protein that plays a role in the assembly of cytochrome C oxidase, an important component of the respiratory pathway. It contains two transmembrane helices and localizes to the mitochondrial membrane. Mutations in this gene can cause mitochondrial complex IV deficiency, which results in ataxia and muscle hypotonia. There are multiple pseudogenes for this gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]
HNRNPU (HGNC:5048): (heterogeneous nuclear ribonucleoprotein U) This gene encodes a member of a family of proteins that bind nucleic acids and function in the formation of ribonucleoprotein complexes in the nucleus with heterogeneous nuclear RNA (hnRNA). The encoded protein has affinity for both RNA and DNA, and binds scaffold-attached region (SAR) DNA. Mutations in this gene have been associated with epileptic encephalopathy, early infantile, 54. A pseudogene of this gene has been identified on chromosome 14. [provided by RefSeq, Jun 2017]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-244842061-G-C is Pathogenic according to our data. Variant chr1-244842061-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 380082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COX20NM_198076.6 linkc.157+3G>C splice_region_variant, intron_variant Intron 2 of 3 ENST00000411948.7 NP_932342.1 Q5RI15-1B3KM21

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COX20ENST00000411948.7 linkc.157+3G>C splice_region_variant, intron_variant Intron 2 of 3 1 NM_198076.6 ENSP00000406327.2 Q5RI15-1

Frequencies

GnomAD3 genomes
AF:
0.000632
AC:
96
AN:
151860
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000266
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000571
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00109
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.000568
AC:
142
AN:
249980
Hom.:
0
AF XY:
0.000606
AC XY:
82
AN XY:
135228
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.0000876
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000185
Gnomad NFE exome
AF:
0.00114
Gnomad OTH exome
AF:
0.000492
GnomAD4 exome
AF:
0.000902
AC:
1295
AN:
1435446
Hom.:
0
Cov.:
25
AF XY:
0.000854
AC XY:
611
AN XY:
715794
show subpopulations
Gnomad4 AFR exome
AF:
0.0000916
Gnomad4 AMR exome
AF:
0.000113
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000187
Gnomad4 NFE exome
AF:
0.00113
Gnomad4 OTH exome
AF:
0.000722
GnomAD4 genome
AF:
0.000632
AC:
96
AN:
151860
Hom.:
0
Cov.:
32
AF XY:
0.000634
AC XY:
47
AN XY:
74134
show subpopulations
Gnomad4 AFR
AF:
0.000266
Gnomad4 AMR
AF:
0.000197
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000571
Gnomad4 NFE
AF:
0.00109
Gnomad4 OTH
AF:
0.000957
Alfa
AF:
0.000386
Hom.:
0
Bravo
AF:
0.000563
EpiCase
AF:
0.000928
EpiControl
AF:
0.000711

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Mitochondrial complex 4 deficiency, nuclear type 11 Pathogenic:6
Jun 17, 2022
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 18, 2020
Undiagnosed Diseases Network, NIH
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 04, 2022
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jun 30, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 09, 2024
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial complex IV deficiency, nuclear type 11 (MIM#619054). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. This variant is predicted to result in an out-of- frame loss of exon 2. RT-PCR experiments using patient cells demonstrates an increased expression of the exon 2 deletion transcript and loss of the full length WT transcript compared with control cells (PMID: 30656193). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (1391 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2; 1 heterozygote, 0 homozygotes). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in multiple affected compound heterozygous individuals (ClinVar, PMIDs: 30656193). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 09, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: COX20 c.157+3G>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. This impact on normal splicing was confirmed experimentally using fibroblasts from a compound heterozygous patient: only mRNA transcripts missing exon 2 could be detected, and full length COX20 mRNA transcripts were completely absent (Otero_2019). Furthermore, no protein products could be detected from these same patient fibroblasts, indicating a complete loss of protein product (Otero_2019). The variant allele was found at a frequency of 0.00057 in 249980 control chromosomes (gnomAD). c.157+3G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Mitochondrial Complex 4 Deficiency, Nuclear Type 11 (e.g. Otero_2019, Chakravorty_2020, Naess_2021). These data indicate that the variant is very likely to be associated with disease.The following publications have been ascertained in the context of this evaluation (PMID: 32999401, 32827528, 30656193). Seven ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, four as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3Uncertain:2
-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 24, 2025
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published mRNA and protein analysis in fibroblasts from an individual with this variant demonstrated an absence of full-length mRNA and COX20 protein (PMID: 30656193); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32999401, 32606554, 32827528, 30656193, 37095481) -

Jan 15, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change falls in intron 2 of the COX20 gene. It does not directly change the encoded amino acid sequence of the COX20 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs367956888, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with clinical features of mitochondrial complex IV deficiency (PMID: 30656193, 32827528, 32999401). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 380082). Studies have shown that this variant alters COX20 gene expression (PMID: 30656193). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 16, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP1_strong, PP3, PM3_very_strong, PS3 -

Mitochondrial complex IV deficiency, nuclear type 1 Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.45
CADD
Benign
15
DANN
Benign
0.91
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.81
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.81
Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs367956888; hg19: chr1-245005363; API