rs1057521790

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_198076.6(COX20):c.41A>G(p.Lys14Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000871 in 1,228,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

COX20
NM_198076.6 missense, splice_region

Scores

Splicing: ADA: 0.9977

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 3.33

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]

COX20 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a chain Cytochrome c oxidase assembly protein COX20, mitochondrial (size 116) in uniprot entity COX20_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_198076.6

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-244835755-A-G is Pathogenic according to our data. Variant chr1-244835755-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 383938.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
COX20	NM_198076.6 link	c.41A>G	p.Lys14Arg	missense_variant, splice_region_variant	Exon 1 of 4	ENST00000411948.7	NP_932342.1	Q5RI15-1B3KM21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COX20	ENST00000411948.7 link	c.41A>G	p.Lys14Arg	missense_variant, splice_region_variant	Exon 1 of 4	1	NM_198076.6	ENSP00000406327.2	Q5RI15-1
COX20	ENST00000391839.6 link	n.100A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 3	1
COX20	ENST00000366528.3 link	c.41A>G	p.Lys14Arg	missense_variant, splice_region_variant	Exon 1 of 5	2		ENSP00000355486.3	Q5RI15-2
COX20	ENST00000498262.1 link	n.97A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.0000470

AC:

AN:

148900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000663

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000404

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000594

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000926

AC:

100

AN:

1079654

Hom.:

Cov.:

AF XY:

0.0000950

AC XY:

AN XY:

515542

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000495

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000875

Gnomad4 OTH exome

AF:

0.000189

GnomAD4 genome

AF:

0.0000470

AC:

AN:

149038

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

72712

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000662

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000405

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000594

Gnomad4 OTH

AF:

0.00

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex 4 deficiency, nuclear type 11

Pathogenic:4

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) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This missense variant within a splice region results in a frameshift and a premature termination codon. The resulting RNA transcript is unstable and results in reduced protein as demonstrated in patient cells (PMID: 33751098). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (107 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative nucleotide change to cysteine at the same position has been observed in gnomAD (v4; 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 and homozygous individuals (ClinVar, PMIDs: 30656193, 33751098). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PS3_Supporting+PM3_Strong+PP1_Strong -

Apr 06, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 18, 2020

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Sep 25, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in the compound heterozygous state in a patient with sensory-dominant axonal neuropathy and static encephalopathy; discussed that this presentation may represent an expansion of the COX20-related disorders phenotype, but additional studies are warranted (Xu et al., 2019); Published functional studies demonstrate this variant affects the splicing of exon one (Otero et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30656193, 32606554, 33751098, 31079202, 35598585, 35651336, 36136859) -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 14 of the COX20 protein (p.Lys14Arg). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with COX20-related neurological disorder (PMID: 30656193, 31079202, 33751098). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 383938). 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 tolerated. Studies have shown that this missense change is associated with altered splicing resulting in multiple RNA products (PMID: 33751098). For these reasons, this variant has been classified as Pathogenic. -

COX20-related disorder

Pathogenic:1

Jan 31, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The COX20 c.41A>G variant is predicted to result in the amino acid substitution p.Lys14Arg. This variant is located near the end of exon 1 and splicing prediction programs predict a splicing defect at the consensus splice site (Alamut Visual Plus v.1.6.1). This variant has been reported in the compound heterozygous and homozygous states in multiple individuals with with sensory neuropathy and has been documented as a founder variant in the eastern Chinese Han population (Otero et al. 2019. PubMed ID: 30656193; Dong et al. 2021. PubMed ID: 33751098). Functional analysis showed that the variant disrupted proper splicing and lead to decreased protein expression (Otero et al. 2019. PubMed ID: 30656193; Dong et al. 2021. PubMed ID: 33751098). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-244999057-A-G). This variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Mar 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.41A>G (p.K14R) alteration is located in exon 1 (coding exon 1) of the COX20 gene. This alteration results from an A to G substitution at nucleotide position 41, causing the lysine (K) at amino acid position 14 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.002% (1/41838) total alleles studied. The highest observed frequency was 0.005% (1/18582) of European (non-Finnish) alleles. This variant has been identified in the homozygous state and in trans with another COX20 variant in individuals with features consistent with COX20-related mitochondrial complex IV deficiency (Chen, 2023; Li, 2022; Ban, 2022; Dong, 2021; Xu, 2019; Otero, 2018). This nucleotide position is highly conserved in available vertebrate species. RNA studies show that this variant causes abnormal splicing (Dong, 2021; Ban, 2022; Li, 2022). Expression and functional studies show significantly decreased levels of COX20 protein as well as reduced enzyme activity and oxygen consumption rate (Otero, 2018; Xu, 2019; Dong, 2021). This missense variant is predicted to be tolerated by in silico analysis. In silico splice site analysis predicts that this nucleotide substitution will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.29

T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;M

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.078

Sift

Benign

0.14

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.0050

B;.

Vest4

0.26

MutPred

0.15

Loss of ubiquitination at K14 (P = 0.002);Loss of ubiquitination at K14 (P = 0.002);

MVP

0.081

MPC

0.033

ClinPred

0.63

GERP RS

4.3

Varity_R

0.12

gMVP

0.069

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.74

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.85

Position offset: 1

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over