NM_198076.6(COX20):c.41A>G (p.Lys14Arg) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 2, 2025
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000436136.8

Allele description [Variation Report for NM_198076.6(COX20):c.41A>G (p.Lys14Arg)]

NM_198076.6(COX20):c.41A>G (p.Lys14Arg)

Genes:

LOC129932912:ATAC-STARR-seq lymphoblastoid silent region 2019 [Gene]
COX20:cytochrome c oxidase assembly factor COX20 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q44

Genomic location:

Preferred name:

NM_198076.6(COX20):c.41A>G (p.Lys14Arg)

HGVS:

NC_000001.11:g.244835755A>G
NG_042825.1:g.5450A>G
NM_001312871.1:c.41A>G
NM_001312872.1:c.41A>G
NM_001312873.1:c.22+19A>G
NM_001312874.1:c.41A>G
NM_198076.6:c.41A>GMANE SELECT
NP_001299800.1:p.Lys14Arg
NP_001299801.1:p.Lys14Arg
NP_001299803.1:p.Lys14Arg
NP_932342.1:p.Lys14Arg
NC_000001.10:g.244999057A>G
NM_198076.4:c.41A>G
NM_198076.5:c.41A>G
NR_132419.1:n.280A>G
p.K14R

Protein change:

K14R; LYS14ARG

Links:

OMIM: 614698.0002; dbSNP: rs1057521790

NCBI 1000 Genomes Browser:

rs1057521790

Molecular consequence:

NM_001312873.1:c.22+19A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001312871.1:c.41A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001312872.1:c.41A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001312874.1:c.41A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_198076.6:c.41A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_132419.1:n.280A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000524560	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 25, 2023)	germline	clinical testing	Citation Link,
SCV003472579	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 2, 2025)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 30656193, 31079202, 33751098, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000524560

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Sep 25, 2023)

germline

clinical testing

Citation Link,

SCV003472579

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 2, 2025)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel pathogenic COX20 variants causing dysarthria, ataxia, and sensory neuropathy.

Otero MG, Tiongson E, Diaz F, Haude K, Panzer K, Collier A, Kim J, Adams D, Tifft CJ, Cui H, Millian Zamora F, Au MG, Graham JM Jr, Buckley DJ, Lewis R, Toro C, Bai R, Turner L, Mathews KD, Gahl W, Pierson TM.

Ann Clin Transl Neurol. 2019 Jan;6(1):154-160. doi: 10.1002/acn3.661.

PubMed [citation]

PMID:: 30656193
PMCID:: PMC6331954

Observation of novel COX20 mutations related to autosomal recessive axonal neuropathy and static encephalopathy.

Xu H, Ji T, Lian Y, Wang S, Chen X, Li S, Yin Y, Dong X.

Hum Genet. 2019 Jul;138(7):749-756. doi: 10.1007/s00439-019-02026-4. Epub 2019 May 11.

PubMed [citation]

PMID:: 31079202

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV000524560.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003472579.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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