16-23544671-C-T

Variant summary

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

The NM_001083614.2(EARS2):โ€‹c.328G>Aโ€‹(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 (โ˜…โ˜…).

Frequency

Genomes: ๐‘“ 0.00022 ( 0 hom., cov: 33)
Exomes ๐‘“: 0.00032 ( 0 hom. )

Consequence

EARS2
NM_001083614.2 missense

Scores

10
6
3

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]

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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
EARS2NM_001083614.2 linkc.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
EARS2ENST00000449606.7 linkc.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:
33
AN:
152240
Hom.:
0
Cov.:
33
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:
61
AN:
234458
Hom.:
0
AF XY:
0.000274
AC XY:
35
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.:
0
Cov.:
31
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:
33
AN:
152240
Hom.:
0
Cov.:
33
AF XY:
0.000175
AC XY:
13
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.:
0
Bravo
AF:
0.000246
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000485
AC:
4
ExAC
AF:
0.000257
AC:
31

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
Dec 09, 2017
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU Mรผnchen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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. -

May 01, 2012
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Apr 13, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 13, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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. -

-
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. -

Jul 15, 2024
Revvity Omics, Revvity
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:3
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) -

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. -

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
T
BayesDel_noAF
Uncertain
-0.030
CADD
Pathogenic
30
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
D
LIST_S2
Pathogenic
0.98
D;.;D;D
M_CAP
Uncertain
0.10
D
MetaRNN
Pathogenic
0.83
D;D;D;D
MetaSVM
Uncertain
-0.24
T
MutationAssessor
Pathogenic
3.5
H;H;.;H
PrimateAI
Uncertain
0.64
T
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
D
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.

Other links and lift over

dbSNP: rs201842633; hg19: chr16-23555992; COSMIC: COSV71943018; API