rs201727231

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_001083614.2(EARS2):c.1547G>A(p.Arg516Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000768 in 1,614,048 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000076 ( 0 hom. )

Consequence

EARS2
NM_001083614.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 4.96

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:

GGA2 (HGNC:16064): (golgi associated, gamma adaptin ear containing, ARF binding protein 2) This gene encodes a member of the Golgi-localized, gamma adaptin ear-containing, ARF-binding (GGA) family. This family includes ubiquitous coat proteins that regulate the trafficking of proteins between the trans-Golgi network and the lysosome. These proteins share an amino-terminal VHS domain which mediates sorting of the mannose 6-phosphate receptors at the trans-Golgi network. They also contain a carboxy-terminal region with homology to the ear domain of gamma-adaptins. This family member may play a significant role in cargo molecules regulation and clathrin-coated vesicle assembly. [provided by RefSeq, Jul 2008]

GGA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.83

PP5

Variant 16-23524396-C-T is Pathogenic according to our data. Variant chr16-23524396-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 265109.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EARS2	NM_001083614.2 link	c.1547G>A	p.Arg516Gln	missense_variant	Exon 9 of 9	ENST00000449606.7	NP_001077083.1	Q5JPH6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EARS2	ENST00000449606.7 link	c.1547G>A	p.Arg516Gln	missense_variant	Exon 9 of 9	1	NM_001083614.2	ENSP00000395196.2	Q5JPH6-1
EARS2	ENST00000564987.1 link	n.1191G>A		non_coding_transcript_exon_variant	Exon 8 of 9	1
EARS2	ENST00000674054.1 link	n.1547G>A		non_coding_transcript_exon_variant	Exon 9 of 10			ENSP00000501251.1	Q5JPH6-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000641

AC:

AN:

249576

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135404

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000759

AC:

111

AN:

1461874

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000962

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000240

AC:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome

Pathogenic:2

Oct 23, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The EARS2 c.1547G>A (p.Arg516Gln) variant has been reported in two individuals affected with Leukoencephalopathy-Thalamus And Brainstem Anomalies-High Lactate Syndrome (Roux CJ et al., PMID: 33972171; Steenweg ME et al., PMID: 22492562). One patient was compound heterozygous for c.1547G>A and a different pathogenic variant (Steenweg ME et al., PMID: 22492562). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.015% in European-non Finnish population. Another variant affecting codon 516, c.1546C>T (p.Arg516Trp), has been reported as pathogenic in two affected brothers (Sahin S et al., PMID: 27206875). An additional variant affecting codon 516, c.1546C>G (p.Arg516Gly), is reported in ClinVar as a variant of uncertain significance (ClinVar Variation ID: 134876). Computational predictors are uncertain as to the impact of this variant on EARS2 function. This variant has been reported in the ClinVar database as pathogenic, likely pathogenic and as a variant of uncertain significance (ClinVar Variation ID:265109). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

Jan 14, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely 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: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Apr 22, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R516Q variant has been previously published in association with leukoencephalopathy with thalmus and brainstem involvement and high lactate (LTBL) in a patient who was compound heterozygous for the two mutations (Steenweg et al., 2012). This patient was described as having a severe phenotype with hypotonia, impaired psychomotor development, dystonia, vision problems, elevated lactate, and seizures (Steenweg et al., 2012). The R516Q variant is a non-conservative amino acid substitution of a positively charged residue with an uncharged residue. We interpret this variant as pathogenic. -

not specified

Uncertain:1

May 18, 2023

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: EARS2 c.1547G>A (p.Arg516Gln) results in a conservative amino acid change located in the Aminoacyl-tRNA synthetase, class I, anticodon-binding domain (IPR045462) 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 6.4e-05 in 249576 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1547G>A has been reported in the literature in compound heterozygous individuals affected with Leukoencephalopathy-Thalamus And Brainstem Anomalies-High Lactate Syndrome (e.g., Steenweg_2012, Roux_2021). These data indicate that the variant may 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: 33128823, 33972171, 22492562). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic (n = 1) or likely pathogenic (n = 2). Additionally, another missense variant affecting the same amino acid, c.1546C>T (p.Arg516Trp), has been reported in the literature in patients affected with Leukoencephalopathy-Thalamus And Brainstem Anomalies-High Lactate Syndrome (PMID: 27206875). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

D;D

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;.

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.79

MVP

0.84

MPC

0.75

ClinPred

0.90

GERP RS

4.7

Varity_R

0.66

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