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

dbSNP: rs184469579

Total submissions: 7

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)
Labcorp Genetics (formerly Invitae), Labcorp	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