Submissions for variant NM_001303.4(COX10):c.624+4A>G

gnomAD frequency: 0.00017  dbSNP: rs199668725

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000288666	SCV000400613	uncertain significance	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, 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.
Illumina Laboratory Services, Illumina	RCV000343670	SCV000400614	uncertain significance	Cytochrome-c oxidase deficiency disease	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, 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.
GeneDx	RCV000829183	SCV000970898	likely benign	not provided	2018-05-11	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.
CeGaT Center for Human Genetics Tuebingen	RCV000829183	SCV001370990	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	COX10: BP4, BS2
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000829183	SCV001468049	uncertain significance	not provided	2020-09-15	criteria provided, single submitter	clinical testing
Invitae	RCV000829183	SCV001498735	uncertain significance	not provided	2022-05-28	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the COX10 gene. It does not directly change the encoded amino acid sequence of the COX10 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs199668725, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with COX10-related conditions. ClinVar contains an entry for this variant (Variation ID: 321815). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.
Baylor Genetics	RCV000288666	SCV001524050	uncertain significance	Leigh syndrome	2019-02-14	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].