Submissions for variant NM_020442.6(VARS2):c.1010C>T (p.Thr337Ile)

gnomAD frequency: 0.00001  dbSNP: rs587777585

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000129937	SCV000680430	pathogenic	Combined oxidative phosphorylation defect type 20	2017-11-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000623604	SCV000740809	pathogenic	Inborn genetic diseases	2014-12-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000129937	SCV001137064	pathogenic	Combined oxidative phosphorylation defect type 20	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001090482	SCV001246055	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001090482	SCV001764381	pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing	Published functional studies in yeast suggest that T367I could result in an OXPHOS-dependent growth defect, with a slightly lower respiration rate in mutants than in wildtype strain (Diodato et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24827421, 29478218, 27502409, 29314548, 30458719, 31623496, 34426522, 27290639, 30925032, 31064326)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001090482	SCV002243757	pathogenic	not provided	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 367 of the VARS2 protein (p.Thr367Ile). This variant is present in population databases (rs587777585, gnomAD 0.009%). This missense change has been observed in individual(s) with clinical features of VARS2-related conditions (PMID: 24827421, 27290639, 27502409, 29314548, 31064326, 31623496). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 141427). 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 VARS2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects VARS2 function (PMID: 24827421). For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000129937	SCV002521733	pathogenic	Combined oxidative phosphorylation defect type 20	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:24827421). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.91; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000141427). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
DASA	RCV000129937	SCV002526415	pathogenic	Combined oxidative phosphorylation defect type 20	2022-06-10	criteria provided, single submitter	clinical testing	The c.1100C>T;p.(Thr367Ile) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 141427; PMID: 24827421; 27290639; 27502409; 29314548; 29478218; 30458719; 30925032; 31064326; 31623496) - .PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 24827421) - PS3_supporting. The variant is present at low allele frequencies population databases (rs587777585– gnomAD 0.0002628%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. The p.(Thr367Ile) was detected in trans with a Pathogenic variant (PMID: 29314548; 29478218; 30458719; 31064326; 31623496) - PM3_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Pathogenic
MGZ Medical Genetics Center	RCV000129937	SCV002579561	pathogenic	Combined oxidative phosphorylation defect type 20	2021-10-22	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000129937	SCV003807337	pathogenic	Combined oxidative phosphorylation defect type 20	2022-07-25	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM3 strong, PP3 supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000129937	SCV004021167	pathogenic	Combined oxidative phosphorylation defect type 20	2023-06-26	criteria provided, single submitter	clinical testing	Variant summary: VARS2 c.1010C>T (p.Thr337Ile) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Aminoacyl-tRNA synthetase, class Ia (IPR002300) of 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 2.4e-05 in 246604 control chromosomes (gnomAD). c.1010C>T has been reported in the literature in multiple individuals affected with mitochondrial disorders (Pronicka_2016, Diodato_2014, Tolomeo_2021, Baertling_2017), including in a compound heterozygous patient with a likely pathogenic variant in trans. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in a yeast model, finding that yeast culture carrying the variant in the orthologous residue had a slower growth rate (Diodato_2014). The following publications have been ascertained in the context of this evaluation (PMID: 27290639, 24639874, 34362006, 27502409). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000129937	SCV000184756	pathogenic	Combined oxidative phosphorylation defect type 20	2014-08-01	no assertion criteria provided	literature only