rs202201763

Positions:

chr6-30920091-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_020442.6(VARS2):c.1168G>A(p.Ala390Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,540,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

VARS2
NM_020442.6 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:5

Conservation

PhyloP100: 8.79

Variant links:

Genes affected

VARS2 (HGNC:21642): (valyl-tRNA synthetase 2, mitochondrial) This gene encodes a mitochondrial aminoacyl-tRNA synthetase, which catalyzes the attachment of valine to tRNA(Val) for mitochondrial translation. Mutations in this gene cause combined oxidative phosphorylation deficiency-20, and are also associated with early-onset mitochondrial encephalopathies. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2014]

VARS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-30920091-G-A is Pathogenic according to our data. Variant chr6-30920091-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522814.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=4, Pathogenic=2}. Variant chr6-30920091-G-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.10521114). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VARS2	NM_020442.6 linkuse as main transcript	c.1168G>A	p.Ala390Thr	missense_variant, splice_region_variant	13/30	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2 linkuse as main transcript	c.1258G>A	p.Ala420Thr	missense_variant, splice_region_variant	13/30		NP_001161206.1
VARS2	NM_001167733.3 linkuse as main transcript	c.748G>A	p.Ala250Thr	missense_variant, splice_region_variant	12/29		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1 linkuse as main transcript	c.1168G>A	p.Ala390Thr	missense_variant, splice_region_variant	13/30		NM_020442.6	ENSP00000502585	P3	Q5ST30-1

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00235

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000402

AC:

AN:

188830

Hom.:

AF XY:

0.000407

AC XY:

AN XY:

100740

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00232

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000181

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.000162

AC:

225

AN:

1388478

Hom.:

Cov.:

AF XY:

0.000149

AC XY:

102

AN XY:

683432

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00235

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000119

Gnomad4 OTH exome

AF:

0.000314

GnomAD4 genome

AF:

0.000374

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00235

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000207

Hom.:

Bravo

AF:

0.000646

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000185

AC:

ExAC

AF:

0.000277

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 20

Pathogenic:4Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 10, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pediatrics, Salzburger Landeskliniken & Paracelsus Medical University	Feb 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	May 04, 2017	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Pathogenic:2Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 12, 2024	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	VARS2: PM3, PM2:Supporting -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	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. -

VARS2-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 03, 2024

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 another individual with a similar phenotype (Kušíková et al. 2021. PubMed ID: 33937156). Experimental studies on muscle homogenate from that patient indicated that VARS2 protein was deficient. This variant is reported in 0.24% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 11, 2021

Bruni, 2018 Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

See cases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Dec 18, 2020

ACMG classification criteria: BS1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

T;.;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Benign

0.042

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Pathogenic

3.9

H;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.5

D;.;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0020

D;.;D

Sift4G

Uncertain

0.010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.65

MVP

0.76

MPC

1.3

ClinPred

0.31

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over