ClinVar Miner

Submissions for variant NM_001303.4(COX10):c.1007A>T (p.Asp336Val)

gnomAD frequency: 0.00006  dbSNP: rs104894557
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München RCV000995747 SCV001150075 pathogenic Mitochondrial complex IV deficiency, nuclear type 1 2018-08-20 criteria provided, single submitter clinical testing
Kids Research, The Children's Hospital at Westmead RCV000995747 SCV001244720 pathogenic Mitochondrial complex IV deficiency, nuclear type 1 criteria provided, single submitter research
Revvity Omics, Revvity RCV000007960 SCV002023377 likely pathogenic Mitochondrial complex 4 deficiency, nuclear type 3 2021-05-27 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000007960 SCV002776313 likely pathogenic Mitochondrial complex 4 deficiency, nuclear type 3 2021-07-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003555963 SCV004296743 likely pathogenic not provided 2024-11-11 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 336 of the COX10 protein (p.Asp336Val). This variant is present in population databases (rs104894557, gnomAD 0.02%). This missense change has been observed in individuals with clinical features consistent with mitochondrial complex IV deficiency (PMID: 12928484, 24100867, 32313153). ClinVar contains an entry for this variant (Variation ID: 7525). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COX10 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects COX10 function (PMID: 22669974, 24100867). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000007960 SCV005204372 likely pathogenic Mitochondrial complex 4 deficiency, nuclear type 3 2024-06-12 criteria provided, single submitter clinical testing Variant summary: COX10 c.1007A>T (p.Asp336Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 250112 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in COX10 causing Mitochondrial Complex 4 Deficiency, Nuclear Type 3, allowing no conclusion about variant significance. c.1007A>T has been reported in the literature in compound heterozygous individuals affected with Cytochrome c oxidase deficiency (Antonicka_2003, Riley_2020). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function and this variant results in a catalytically inactive enzyme (Khalimonchuk_2012, Pitceathly_2013). The following publications have been ascertained in the context of this evaluation (PMID: 12928484, 22669974, 24100867, 32313153). ClinVar contains an entry for this variant (Variation ID: 7525). Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM RCV000007960 SCV000028165 pathogenic Mitochondrial complex 4 deficiency, nuclear type 3 2003-10-15 no assertion criteria provided literature only
Johnston Lab, North Central College RCV003555963 SCV005200372 not provided not provided no assertion provided in vitro

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