Submissions for variant NM_078470.6(COX15):c.211C>T (p.Arg71Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002472112	SCV002768521	likely pathogenic	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2	2022-09-02	criteria provided, single submitter	clinical testing	A heterozygous nonsense variant was identified, NM_004376.5(COX15):c.211C>T in exon 2 of 9 of the COX15gene. (NB: This variant is non-coding in NM_001320976.1). This nonsense variant is predicted to create a change of arginine to a stop at amino acid position 71 of the protein, NP_004367.2(COX15):p.(Arg71*), resulting in the loss of normal protein function through nonsense-mediated decay (NMD). The variant is present in the gnomAD population database at a frequency of 0.0028% (8 heterozygotes, 0 homozygotes). It has not been previously reported in clinical cases. Two other variants predicted to cause NMD have been reported as pathogenic in individuals with this condition (ClinVar, Alfadhel, M., et al. (2011), Invernizzi, F., et al. (2012)). Analysis of parental samples indicates that this variant is maternally inherited. Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC.
Revvity Omics, Revvity	RCV002472112	SCV003829919	uncertain significance	Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2	2019-05-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV005098460	SCV005801432	pathogenic	not provided	2024-05-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg71*) in the COX15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COX15 are known to be pathogenic (PMID: 15863660, 21412973). This variant is present in population databases (rs751819645, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with COX15-related conditions. ClinVar contains an entry for this variant (Variation ID: 1805694). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.