16-23544679-C-T

Variant names:

• chr16-23544679-C-T
• rs1021330566
• NM_001083614.2:c.320G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PM1 PM2 PM5 PP5_Very_Strong BP4

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. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R107C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: EARS2 NM_001083614.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 2.46
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001083614.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-23544680-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 973188.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP5: Variant 16-23544679-C-T is Pathogenic according to our data. Variant chr16-23544679-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId 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 rank	MANE	Protein	UniProt
EARS2	NM_001083614.2	c.320G>A	p.Arg107His	missense_variant	Exon 3 of 9	ENST00000449606.7	NP_001077083.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EARS2	ENST00000449606.7	c.320G>A	p.Arg107His	missense_variant	Exon 3 of 9	1	NM_001083614.2	ENSP00000395196.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 229532 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 26 AN: 1453524 Hom.: 0 Cov.: 31 AF XY: 0.0000208 AC XY: 15 AN XY: 722418

African (AFR) AF: 0.00 AC: 0 AN: 33366

American (AMR) AF: 0.00 AC: 0 AN: 43320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25878

East Asian (EAS) AF: 0.00 AC: 0 AN: 39490

South Asian (SAS) AF: 0.00 AC: 0 AN: 85044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4696

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1109252

Other (OTH) AF: 0.00 AC: 0 AN: 60042

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41482

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Oct 25, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Studies have shown that this missense change alters EARS2 gene expression (PMID: 26780086). 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. -

May 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome Pathogenic:3

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Dec 09, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	23
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	D
LIST_S2	Uncertain	0.92	D;.;D;D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;.;L
PhyloP100		2.5
PrimateAI	Benign	0.42	T
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	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.68
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1021330566; hg19: chr16-23556000;