16-23544671-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_001083614.2(EARS2):c.328G>A(p.Gly110Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 1,607,912 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

EARS2
NM_001083614.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.54

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

PP5

Variant 16-23544671-C-T is Pathogenic according to our data. Variant chr16-23544671-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 39789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EARS2	NM_001083614.2 link	c.328G>A	p.Gly110Ser	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.328G>A	p.Gly110Ser	missense_variant	Exon 3 of 9	1	NM_001083614.2	ENSP00000395196.2		Q5JPH6-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000260

AC:

AN:

234458

Hom.:

AF XY:

0.000274

AC XY:

AN XY:

127740

show subpopulations

Gnomad AFR exome

AF:

0.000214

Gnomad AMR exome

AF:

0.0000302

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000340

Gnomad FIN exome

AF:

0.0000508

Gnomad NFE exome

AF:

0.000520

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000318

AC:

463

AN:

1455672

Hom.:

Cov.:

AF XY:

0.000321

AC XY:

232

AN XY:

723712

show subpopulations

Gnomad4 AFR exome

AF:

0.000210

Gnomad4 AMR exome

AF:

0.0000229

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.000398

Gnomad4 OTH exome

AF:

0.000183

GnomAD4 genome

AF:

0.000217

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000371

Hom.:

Bravo

AF:

0.000246

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000485

AC:

ExAC

AF:

0.000257

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Pathogenic:8

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.G110S in EARS2 (NM_001083614.2) has been reported previously in association with infantileonset mitochondrial encephalopathy when present in trans with another disease-causing variant in the EARS2 gene (Steenweg et al., 2012; Danhauser et al., 2016). Studies on patient-derived skin fibroblasts showed severely decreased EARS2 protein levels, elevated reactive oxygen species production, and altered mitochondrial morphology (Danhauser et al., 2016). This variant was found in ClinVar with a classification of Pathogenic/Likely Pathogenic. There is a small physicochemical difference between glycine and serine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.G110S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 110 of EARS2 is conserved in all mammalian species. The nucleotide c.328 in EARS2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -

Oct 13, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 13, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 17, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: EARS2 c.328G>A (p.Gly110Ser) 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. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 234458 control chromosomes (gnomAD). c.328G>A has been reported in the literature in individuals affected with EARS2 related disorders (example: Steenweg_2012 , Danhauser_2016, McNeil_2017, Prasun_2019). These data indicate that the variant is likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Dec 17, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EARS2 c.328G>A (p.Gly110Ser) variant has been reported in two studies and is found in a total of three probands in a compound heterozygous state (Steenweg et al. 2012; Danhauser et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.00061 in the European (non-Finnish) population of the Exome Aggregation Consortium. Analysis of proband fibroblasts revealed lower EARS2 protein levels and higher mitochondrial ROS when compared to control fibroblasts. Based on the collective evidence, the p.Gly110Ser variant is classified as likely pathogenic for combined oxidative phosphorylation deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Jul 15, 2024

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2017

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Feb 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 110 of the EARS2 protein (p.Gly110Ser). This variant is present in population databases (rs201842633, gnomAD 0.05%). This missense change has been observed in individual(s) with combined oxidative phosphorylation deficiency (PMID: 22492562). 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: 39789). 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 EARS2 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Mar 03, 2025

GeneDx

Significance: Likely 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: 26741492, 26780086, 28748214, 26619324, 25854774, 25058219, 23008233, 31980526, 33128823, 22492562, 28748215, 33962821, 31520968, 39173847) -

Jun 25, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP4, PM1, PM2, PM3_strong, PS4_moderate -

Inborn genetic diseases

Pathogenic:1

Jun 25, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.328G>A (p.G110S) alteration is located in exon 3 (coding exon 3) of the EARS2 gene. This alteration results from a G to A substitution at nucleotide position 328, causing the glycine (G) at amino acid position 110 to be replaced by a serine (S). Based on data from the Genome Aggregation Database (gnomAD), the EARS2 c.328G>A alteration was observed in 0.03% (69/265858) of total alleles studied, with a frequency of 0.05% (61/121100) in the European (non-Finnish) subpopulation. This alteration was previously reported in the compound heterozygous state with a second pathogenic EARS2 alteration in multiple patients with clinical features of mitochondrial glutamyl-tRNA synthetase deficiency and clinical severity ranging from the less severe disease course of developmental delay, abnormal brain MRI, childhood onset spasticity and seizures to a more severe disease course of fatal neonatal lactic acidosis (Steenweg, 2012; Danhauser, 2016; Prasun, 2019). The p.G110 amino acid is completely conserved in available vertebrate species. Functional studies in patient-derived skin fibroblasts have demonstrated decreased EARS2 protein levels and evidence of mitochondrial dysfunction including increased reactive oxygen species production and increased mitochondrial mass (Danhauser, 2016). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;D;D;.

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;.;D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.83

D;D;D;D

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.5

H;H;.;H

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.8

D;D;D;D

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.90

MVP

0.76

MPC

0.69

ClinPred

0.95

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.88

gMVP

0.90

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