Submissions for variant NM_078470.6(COX15):c.164G>A (p.Arg55Lys)

gnomAD frequency: 0.00004  dbSNP: rs777532861

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197287	SCV000251293	likely benign	not specified	2012-02-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Laboratory Services, Illumina	RCV000291406	SCV000359745	uncertain significance	Leigh syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV002515389	SCV003252679	uncertain significance	not provided	2022-03-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 55 of the COX15 protein (p.Arg55Lys). This variant is present in population databases (rs777532861, gnomAD 0.2%). 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: 214255). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002517204	SCV003678865	uncertain significance	Inborn genetic diseases	2020-11-05	criteria provided, single submitter	clinical testing	The c.164G>A (p.R55K) alteration is located in exon 2 (coding exon 2) of the COX15 gene. This alteration results from a G to A substitution at nucleotide position 164, causing the arginine (R) at amino acid position 55 to be replaced by a lysine (K). Based on data from the Genome Aggregation Database (gnomAD) database, the COX15 c.164G>A alteration was observed in 0.01% (23/282860) of total alleles studied, with a frequency of 0.2% (21/10370) in the Ashkenazi Jewish subpopulation. This amino acid position is not well conserved in available vertebrate species. The p.R55K alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.