Submissions for variant NM_017646.6(TRIT1):c.1225G>A (p.Glu409Lys)

gnomAD frequency: 0.00001  dbSNP: rs764506732

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001566429	SCV001789942	likely pathogenic	not provided	2024-06-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36768505, Cheon (2022)_ article, 32948376)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001566429	SCV004512290	likely pathogenic	not provided	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 409 of the TRIT1 protein (p.Glu409Lys). This variant is present in population databases (rs764506732, gnomAD 0.008%). This missense change has been observed in individual(s) with TRIT1-related conditions (PMID: 32948376). 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 also known as c.979G>A (p.Glu327Lys). ClinVar contains an entry for this variant (Variation ID: 1201174). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TRIT1 protein function with a positive predictive value of 80%. 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV004728774	SCV005329535	likely pathogenic	Combined oxidative phosphorylation deficiency 35	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense variant c.1225G>A(p.Glu409Lys) in TRIT1 gene has been reported previously in compound heterozygousstate in siblings with Combined oxidative phosphorylation deficiency (Yoo S, et al., 2021). Protein structure analysis revealed thatthis variant disrupts the conformation and electrostatic charge of the zinc-finger motif in the tRNA isopentenyltransferase (IPT),impairing binding of the mutant IPT to specific DNA sequences (Yoo S, et al., 2021).The c.1225G>A variant has 0.001% allele frequencyin gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic. Multiple lines of computationalevidence (Polyphen, SIFT and Mutation Taster) predict a damaging effect on protein structure and function for this variant. Theamino acid Glutamine at position 409 is changed to a Lysine changing protein sequence and it might alter its composition andphysico-chemical properties. The amino acid change p.Glu409Lys in TRIT1 is predicted as conserved by GERP++ and PhyloP across100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.