ClinVar Miner

Submissions for variant NM_012123.4(MTO1):c.1462C>T (p.Arg488Ter)

gnomAD frequency: 0.00002  dbSNP: rs771939280
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000579188 SCV000680967 pathogenic not provided 2019-10-14 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31842146)
Ambry Genetics RCV002530369 SCV003618803 pathogenic Inborn genetic diseases 2022-06-17 criteria provided, single submitter clinical testing The c.1582C>T (p.R528*) alteration, located in exon 9 (coding exon 9) of the MTO1 gene, consists of a C to T substitution at nucleotide position 1582. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 528. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration was detected in trans with an MTO1 missense alteration in two siblings with MTO1-related combined oxidative phosphorylation deficiency (Li, 2020). Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV003532177 SCV004300413 pathogenic Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency 2023-06-07 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 488996). This premature translational stop signal has been observed in individual(s) with combined oxidative phosphorylation deficiency (PMID: 31842146). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs771939280, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg488*) in the MTO1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MTO1 are known to be pathogenic (PMID: 22608499, 25058219).

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