6-30918851-C-T

Position:

chr6-30918851-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_020442.6(VARS2):c.1010C>T(p.Thr337Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,612,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

VARS2
NM_020442.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 7.12

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

PP5

Variant 6-30918851-C-T is Pathogenic according to our data. Variant chr6-30918851-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 141427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-30918851-C-T is described in UniProt as null. Variant chr6-30918851-C-T is described in Lovd as [Pathogenic]. Variant chr6-30918851-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
VARS2	NM_020442.6 linkuse as main transcript	c.1010C>T	p.Thr337Ile	missense_variant	11/30	ENST00000676266.1	NP_065175.4
VARS2	NM_001167734.2 linkuse as main transcript	c.1100C>T	p.Thr367Ile	missense_variant	11/30		NP_001161206.1
VARS2	NM_001167733.3 linkuse as main transcript	c.590C>T	p.Thr197Ile	missense_variant	10/29		NP_001161205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VARS2	ENST00000676266.1 linkuse as main transcript	c.1010C>T	p.Thr337Ile	missense_variant	11/30		NM_020442.6	ENSP00000502585	P3	Q5ST30-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000243

AC:

AN:

246604

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134424

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.0000181

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000233

AC:

AN:

1460716

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726672

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

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:

0.0000270

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000254

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined oxidative phosphorylation defect type 20

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 26, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jul 25, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM3 strong, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 16, 2017	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 05, 2024	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. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

T;.;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Uncertain

0.38

MutationAssessor

Pathogenic

4.8

H;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-5.7

D;.;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.96

MVP

0.68

MPC

1.4

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.86

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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