rs376103091

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001083614.2(EARS2):c.322C>T(p.Arg108Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,606,474 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

EARS2
NM_001083614.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12O:1

Conservation

PhyloP100: 3.54

Variant links:

Genes affected

EARS2 (HGNC:29419): (glutamyl-tRNA synthetase 2, mitochondrial) This gene encodes a member of the class I family of aminoacyl-tRNA synthetases. These enzymes play a critical role in protein biosynthesis by charging tRNAs with their cognate amino acids. This protein is encoded by the nuclear genome but is likely to be imported to the mitochondrion where it is thought to catalyze the ligation of glutamate to tRNA molecules. Mutations in this gene have been associated with combined oxidative phosphorylation deficiency 12 (COXPD12). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]

EARS2 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-23544677-G-A is Pathogenic according to our data. Variant chr16-23544677-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-23544677-G-A is described in Lovd as [Likely_pathogenic]. Variant chr16-23544677-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EARS2	NM_001083614.2 link	c.322C>T	p.Arg108Trp	missense_variant	Exon 3 of 9	ENST00000449606.7	NP_001077083.1	Q5JPH6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EARS2	ENST00000449606.7 link	c.322C>T	p.Arg108Trp	missense_variant	Exon 3 of 9	1	NM_001083614.2	ENSP00000395196.2		Q5JPH6-1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000151

AC:

AN:

231208

Hom.:

AF XY:

0.000167

AC XY:

AN XY:

126014

show subpopulations

Gnomad AFR exome

AF:

0.0000729

Gnomad AMR exome

AF:

0.0000612

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000137

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000269

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000142

AC:

207

AN:

1454244

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

110

AN XY:

722864

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000690

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000106

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000166

Gnomad4 OTH exome

AF:

0.000117

GnomAD4 genome

AF:

0.000184

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000189

Hom.:

Bravo

AF:

0.000166

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000486

AC:

ExAC

AF:

0.000149

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Pathogenic:5Other:1

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000039787). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 22492562). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Dec 20, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: EARS2 c.322C>T (p.Arg108Trp) results in a non-conservative amino acid change located in the glutamyl/glutaminyl-tRNA synthetase, class Ib, catalytic domain (IPR020058) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 231208 control chromosomes. c.322C>T has been reported in the literature in multiple individuals affected with and/or with clinical features of Leukoencephalopathy-Thalamus And Brainstem Anomalies-High Lactate Syndrome (e.g. Steenweg_2012, Taylor_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22492562, 25058219). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 14, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.322C>T (p.Arg108Trp) in the EARS2 gene has been reported previously in heterozygous and compound heterozygous state in individuals affected with Leukoencephalopathy. It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported (Steenweg et al., 2012; Taskin et al., 2016) Missense changes are a common disease-causing mechanism. This variant is reported with the allele frequency (0.01%) in the gnomAD and novel (not in any individuals) in the 1000 genome database. It is submitted to ClinVar with varying interpretations as Likely Pathogenic/ Pathogenic (Multiple Submissions). The amino acid Arginine at position 108 is changed to a Tryptophan changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Arg108Trp in EARS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:4

Mar 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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: 27571996, 27875839, 33855712, 33972171, 22492562, 26893310, 25058219, 27374853, 31520968, 34440436) -

Sep 13, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 108 of the EARS2 protein (p.Arg108Trp). This variant is present in population databases (rs376103091, gnomAD 0.03%). This missense change has been observed in individual(s) with combined oxidative phosphorylation deficiency (PMID: 22492562, 26893310). 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: 39787). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt EARS2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Jun 07, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Sep 11, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases

Pathogenic:1

Dec 21, 2022

Center for Personalized Medicine, Children's Hospital Los Angeles

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seizure;C0235081:Limb tremor;C0240635:High palate;C0424503:Abnormal facial shape;C0494475:Bilateral tonic-clonic seizure;C0557874:Global developmental delay;C0857379:Abnormal pinna morphology;C1837260:Prominent forehead;C1854301:Motor delay

Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

D;D;D;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.97

D;.;D;D

M_CAP

Benign

0.027

MetaRNN

Uncertain

0.43

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.5

M;M;.;M

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.9

D;D;D;D

REVEL

Benign

0.19

Sift

Benign

0.11

T;T;T;T

Sift4G

Benign

0.18

T;T;T;T

Polyphen

0.99

D;D;.;.

Vest4

0.55

MVP

0.61

MPC

0.63

ClinPred

0.24

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.15

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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