NM_198076.6:c.157+3G>C

Variant names:

• chr1-244842061-G-C
• rs367956888
• NM_198076.6:c.157+3G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 U:3
• Conservation: PhyloP100: 1.62
• Publications: 7 publications found

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]

HNRNPU Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 54

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-244842061-G-C is Pathogenic according to our data. Variant chr1-244842061-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 380082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198076.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX20	NM_198076.6	MANE Select	c.157+3G>C		splice_region intron	N/A	NP_932342.1
	COX20	NM_001312872.1		c.193+3G>C		splice_region intron	N/A	NP_001299801.1
	COX20	NM_001312871.1		c.157+3G>C		splice_region intron	N/A	NP_001299800.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX20	ENST00000411948.7	TSL:1 MANE Select	c.157+3G>C		splice_region intron	N/A	ENSP00000406327.2
	COX20	ENST00000391839.6	TSL:1	n.102-134G>C		intron	N/A
	HNRNPU	ENST00000366527.4	TSL:2	n.11429C>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.000632 AC: 96 AN: 151860 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000568 AC: 142 AN: 249980 AF XY: 0.000606

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 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

African (AFR) AF: 0.0000916 AC: 3 AN: 32756

American (AMR) AF: 0.000113 AC: 5 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00 AC: 0 AN: 39528

South Asian (SAS) AF: 0.00 AC: 0 AN: 85434

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.00113 AC: 1234 AN: 1088900

Other (OTH) AF: 0.000722 AC: 43 AN: 59516

GnomAD4 genome AF: 0.000632 AC: 96 AN: 151860 Hom.: 0 Cov.: 32 AF XY: 0.000634 AC XY: 47 AN XY: 74134

African (AFR) AF: 0.000266 AC: 11 AN: 41340

American (AMR) AF: 0.000197 AC: 3 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.000571 AC: 6 AN: 10514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 67966

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

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:12 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 11 Pathogenic:8

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 17, 2025

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 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. The variant allele was found at a frequency of 0.00057 in 249980 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in COX20 causing Mitochondrial Complex 4 Deficiency, Nuclear Type 11, allowing no conclusion about variant significance. c.157+3G>C has been observed 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). ClinVar contains an entry for this variant (Variation ID: 380082). Based on the evidence outlined above, the variant was classified as pathogenic.

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

Apr 01, 2025

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 20, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Feb 04, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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

not provided Pathogenic:4 Uncertain:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

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

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.

Sep 19, 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, 35651336)

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.91
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=2/98	disease causing

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

Other links and lift over

dbSNP: rs367956888; hg19: chr1-245005363;