rs1021330566

Positions:

chr16-23544679-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_001083614.2(EARS2):c.320G>A(p.Arg107His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,605,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

EARS2
NM_001083614.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 2.46

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 Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-23544679-C-T is Pathogenic according to our data. Variant chr16-23544679-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 449533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.21801662). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EARS2	NM_001083614.2 linkuse as main transcript	c.320G>A	p.Arg107His	missense_variant	3/9	ENST00000449606.7	NP_001077083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EARS2	ENST00000449606.7 linkuse as main transcript	c.320G>A	p.Arg107His	missense_variant	3/9	1	NM_001083614.2	ENSP00000395196	P1	Q5JPH6-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000179

AC:

AN:

1453524

Hom.:

Cov.:

AF XY:

0.0000208

AC XY:

AN XY:

722418

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000234

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 15, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg107 amino acid residue in EARS2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26741492, 34440436). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Studies have shown that this missense change alters EARS2 gene expression (PMID: 26780086). 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 not expected to disrupt EARS2 protein function. ClinVar contains an entry for this variant (Variation ID: 449533). This missense change has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 22492562, 26780086). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 107 of the EARS2 protein (p.Arg107His). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2017	The R107H variant in the EARS2 gene has been reported previously in the compound heterozygous state along with another EARS2 variant in a few patients with infantile-onset mitochondrial encephalopathy (Steenweg et al., 2012; Danhauser et al., 2016). The R107H variant is not observed in large population cohorts (Lek et al., 2016). The R107H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R107H as a likely pathogenic variant. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2021	- -

Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 09, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 19, 2022	The EARS2 c.320G>A variant is a single nucleotide change in exon 3/9 of the EARS2 gene, which is predicted to change the amino acid arginine at position 107 in the protein to histidine. The variant is rare in population databases (gnomAD allele frequency = 0.00065%; 1 het and 0 hom in 152250 sequenced alleles) (PM2). This variant has been detected in trans with another likely pathogenic variant NM_001083614.2:c.212del in this patient. This variant has also been reported twice in the literature in patients with neonatal hypoglycemia, severe lactic acidosis and corpus callosum agenesis: in trans with c.1A>G (PMID: 22492562) and c.328G>A / p.(Gly110Ser) (PMID: 26780086) (PM3_Strong). Functional studies in patient-derived fibroblasts demonstrated elevated ROS production in patient cells compared to several control cell lines, suggesting altered redox homeostasis (PMID: 26780086) (PS3_supporting). This variant is a novel missense change at an amino acid residue where a different likely pathogenic missense change has been seen before (c.319C>T; p.R107C) (PMID: 26741492) (PM5). The variant has been reported in dbSNP (rs1021330566) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 449533). It has been reported in HGMD (CM123408). -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with combined oxidative phosphorylation deficiency 12 (MIM#614924). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0600 - Variant is located in the annotated tRNA synthetases class I (E and Q), catalytic domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic in ClinVar. It has also been reported in two compound heterozygous individuals with EARS2-related disorders in the literature (PMID: 22492562, 26780086). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. A clear decrease in EARS2 protein levels, increase in mitochondrial mass and an elevated ROS production was demonstrated in patient-derived fibroblast with this variant and a different EARS2 variant on the other allele (PMID: 26780086). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. p.(Arg107Cys) has previously been reported as likely pathogenic (ClinVar) however was not used as supporting evidence as this substitution constitutes are bigger amino acid change. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.42

T;T;T;.

Eigen

Benign

-0.088

Eigen_PC

Benign

0.043

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

D;.;D;D

M_CAP

Benign

0.0086

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;.;L

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Benign

0.017

Sift

Benign

0.54

T;T;T;T

Sift4G

Benign

0.54

T;T;T;T

Polyphen

0.010

B;B;.;.

Vest4

0.27

MutPred

0.45

Loss of glycosylation at P106 (P = 0.1631);Loss of glycosylation at P106 (P = 0.1631);Loss of glycosylation at P106 (P = 0.1631);Loss of glycosylation at P106 (P = 0.1631);

MVP

0.48

MPC

0.23

ClinPred

0.64

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.070

gMVP

0.68

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