Submissions for variant NM_078470.6(COX15):c.*1126T>C

gnomAD frequency: 0.83974  dbSNP: rs2231687

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000116814	SCV000168013	benign	not specified	2011-07-01	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	RCV000259999	SCV000359736	benign	Leigh syndrome	2018-01-13	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000116814	SCV000917264	benign	not specified	2018-09-10	criteria provided, single submitter	clinical testing	Variant summary: COX15 c.1120T>C (p.Phe374Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.86 in 273702 control chromosomes (gnomAD), suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 690-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in COX15 causing Leigh Syndrome phenotype (0.0013), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1120T>C in individuals affected with Leigh Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submission from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000676871	SCV001727390	benign	not provided	2025-02-03	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000676871	SCV005320679	benign	not provided		criteria provided, single submitter	not provided
Genetic Services Laboratory, University of Chicago	RCV000116814	SCV000150888	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Mayo Clinic Laboratories, Mayo Clinic	RCV000676871	SCV000802684	benign	not provided	2016-02-15	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000116814	SCV001742491	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000116814	SCV001956636	benign	not specified		no assertion criteria provided	clinical testing