ClinVar Miner

Submissions for variant NM_017646.6(TRIT1):c.22C>T (p.Arg8Ter)

dbSNP: rs184469579
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
SIB Swiss Institute of Bioinformatics RCV000584740 SCV000883202 likely pathogenic Combined oxidative phosphorylation deficiency 35 2018-10-15 criteria provided, single submitter curation This variant is interpreted as Likely Pathogenic, for Combined oxidative phosphorylation deficiency 35, autosomal recessive. The following ACMG Tag(s) were applied: PM2-Supporting => PM2 downgraded in strength to Supporting. PVS1-Strong => PVS1 downgraded in strength to Strong. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (https://www.ncbi.nlm.nih.gov/pubmed/28185376).
GeneDx RCV001796068 SCV002032685 likely pathogenic not provided 2022-12-28 criteria provided, single submitter clinical testing Identified in trans with a missense variant, in siblings with neurological disease in published literature (Kernohan et al., 2017); 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; This variant is associated with the following publications: (PMID: 28185376, 32948376, 36049610, 36047296, 34052969)
Invitae RCV001796068 SCV002243010 pathogenic not provided 2023-05-12 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: 417684). This premature translational stop signal has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 28185376, 34052969). This variant is present in population databases (rs184469579, gnomAD 0.06%). This sequence change creates a premature translational stop signal (p.Arg8*) in the TRIT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRIT1 are known to be pathogenic (PMID: 24901367, 28185376).
Ambry Genetics RCV002526505 SCV003701496 likely pathogenic Inborn genetic diseases 2022-09-19 criteria provided, single submitter clinical testing The c.22C>T (p.R8*) alteration, located in exon 1 (coding exon 1) of the TRIT1 gene, consists of a C to T substitution at nucleotide position 22. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 8. The predicted stop codon occurs within the first 150 nucleotides of the TRIT1 gene. This alteration may escape nonsense-mediated mRNA decay and/or be rescued by re-initiation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017). However, the impacted region is critical for protein function (Ambry internal data). This variant has been confirmed in trans with another TRIT1 variant in two siblings with acquired microcephaly and seizures (Kernohan, 2017). Based on internal structural analysis, the N-terminal residues 1-56 of TRIT1 contain a mitochrondrial targeting sequence which is critical to full function of the protein (Yarham, 2014; Khalique, 2020). Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics RCV000584740 SCV005049810 pathogenic Combined oxidative phosphorylation deficiency 35 2023-12-08 criteria provided, single submitter clinical testing
Care4Rare-SOLVE, CHEO RCV000477658 SCV000564084 uncertain significance TRIT1 Deficiency no assertion criteria provided research This variant was seen in a heterozygous state with c.856A>G.
OMIM RCV000584740 SCV000692463 pathogenic Combined oxidative phosphorylation deficiency 35 2018-02-16 no assertion criteria provided literature only

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