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

gnomAD frequency: 0.00004  dbSNP: rs1057521790

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000436136	SCV000524560	pathogenic	not provided	2023-09-25	criteria provided, single submitter	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)
Undiagnosed Diseases Network, NIH	RCV001526452	SCV001736865	pathogenic	Mitochondrial complex 4 deficiency, nuclear type 11	2020-12-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000436136	SCV003472579	pathogenic	not provided	2025-02-02	criteria provided, single submitter	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.
PreventionGenetics, part of Exact Sciences	RCV003401423	SCV004104107	pathogenic	COX20-related disorder	2023-01-31	criteria provided, single submitter	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.
Ambry Genetics	RCV004022381	SCV004851832	pathogenic	Inborn genetic diseases	2024-03-05	criteria provided, single submitter	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001526452	SCV005398920	pathogenic	Mitochondrial complex 4 deficiency, nuclear type 11	2024-10-09	criteria provided, single submitter	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	RCV001526452	SCV005416309	pathogenic	Mitochondrial complex 4 deficiency, nuclear type 11		criteria provided, single submitter	clinical testing	PM2_Supporting+PS3_Supporting+PM3_Strong+PP1_Strong
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005355750	SCV005916786	uncertain significance	Mitochondrial disease	2021-12-22	criteria provided, single submitter	research
OMIM	RCV001526452	SCV002073672	pathogenic	Mitochondrial complex 4 deficiency, nuclear type 11	2023-04-06	no assertion criteria provided	literature only