Submissions for variant NM_020442.6(VARS2):c.1168G>A (p.Ala390Thr)

gnomAD frequency: 0.00039  dbSNP: rs202201763

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Undiagnosed Diseases Network, NIH	RCV000625984	SCV000746589	uncertain significance	Combined oxidative phosphorylation defect type 20	2017-05-04	criteria provided, single submitter	clinical testing	This variant was found in trans with another variant (c.1076-14A>G) in a 6-year-old male with severe neurodevelopmental impairment, encephalopathy, microcephaly, hypertrophic cardiomyopathy, lactic acidosis, seizure disorder (infantile spasms), abnormal MRI showing brain and brainstem atrophy.
Mendelics	RCV000625984	SCV001137065	pathogenic	Combined oxidative phosphorylation defect type 20	2019-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000676486	SCV001987432	likely pathogenic	not provided	2024-05-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33937156, 34484863, 31623496, 29314548, 30458719, 34216551)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000676486	SCV002304175	pathogenic	not provided	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 420 of the VARS2 protein (p.Ala420Thr). This variant is present in population databases (rs202201763, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of VARS2-related conditions (PMID: 29314548, 33937156; Invitae). 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. ClinVar contains an entry for this variant (Variation ID: 522814). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002252181	SCV002523926	uncertain significance	See cases	2020-12-18	criteria provided, single submitter	clinical testing	ACMG classification criteria: BS1
CeGaT Center for Human Genetics Tuebingen	RCV000676486	SCV002586104	uncertain significance	not provided	2022-08-01	criteria provided, single submitter	clinical testing	VARS2: PM3, PM2:Supporting
Ambry Genetics	RCV002529769	SCV003681574	uncertain significance	Inborn genetic diseases	2021-08-11	criteria provided, single submitter	clinical testing	Bruni, 2018 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004547763	SCV004119278	likely pathogenic	VARS2-related disorder	2023-05-09	criteria provided, single submitter	clinical testing	The VARS2 c.1258G>A variant is predicted to result in the amino acid substitution p.Ala420Thr. This variant was reported in the homozygous state in two siblings and an apparently unrelated individual with VARS2-related mitochondrial disease (Bruni et al 2018. PubMed ID: 29314548). This variant was also reported, with alternative nomenclature (NM_020442.6:c.1168G>A; p.Ala390Thr), in the compound heterozygous state in a fourth individual with a related phenotype. (Kušíková K et al 2021. PubMed ID: 33937156). Experimental studies on muscle homogenate from this patient indicated that VARS2 protein was deficient. This variant is reported in 0.24% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-30887868-G-A). This variant is interpreted as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000625984	SCV004241293	likely pathogenic	Combined oxidative phosphorylation defect type 20	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: VARS2 c.1168G>A (p.Ala390Thr) results in a non-conservative amino acid change located in the Aminoacyl-tRNA synthetase, class Ia domain (IPR002300) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 1534628 control chromosomes (gnomAD V4.0). The variant, c.1168G>A (aka. c.1258G>A, p.Ala420Thr), has been reported in the literature in multiple individuals affected with Combined Oxidative Phosphorylation Defect Type 20 (Bruni_2018, Kusikova_2021). One of these publications reported that VARS2 protein was deficient in patient derived muscle biopsy, and the resulting defect of oxidative phosphorylation was also demonstrated by enzymatic assay (Kusikova_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 29314548, 33937156, 34216551). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000676486	SCV000802269	uncertain significance	not provided	2017-10-25	no assertion criteria provided	clinical testing
OMIM	RCV000625984	SCV001372473	pathogenic	Combined oxidative phosphorylation defect type 20	2020-07-10	no assertion criteria provided	literature only
Department of Pediatrics, Salzburger Landeskliniken & Paracelsus Medical University	RCV000625984	SCV001481167	pathogenic	Combined oxidative phosphorylation defect type 20	2021-02-22	no assertion criteria provided	clinical testing