rs199589947

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_015340.4(LARS2):c.1565C>A(p.Thr522Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000348 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T522A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

LARS2
NM_015340.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16O:1

Conservation

PhyloP100: 7.54

Publications

29 publications found

Variant links:

Genes affected

LARS2 (HGNC:17095): (leucyl-tRNA synthetase 2, mitochondrial) This gene encodes a class 1 aminoacyl-tRNA synthetase, mitochondrial leucyl-tRNA synthetase. Each of the twenty aminoacyl-tRNA synthetases catalyzes the aminoacylation of a specific tRNA or tRNA isoaccepting family with the cognate amino acid. [provided by RefSeq, Jul 2008]

LARS2 links:

LARS2-AS1 (HGNC:40796): (LARS2 antisense RNA 1)

LARS2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP5

Variant 3-45496316-C-A is Pathogenic according to our data. Variant chr3-45496316-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55871.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
LARS2	NM_015340.4 link	c.1565C>A	p.Thr522Asn	missense_variant	Exon 14 of 22	ENST00000645846.2	NP_056155.1	Q15031

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2 link	c.1565C>A	p.Thr522Asn	missense_variant	Exon 14 of 22		NM_015340.4	ENSP00000495093.1		Q15031

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000302

AC:

AN:

251490

AF XY:

0.000258

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000358

AC:

524

AN:

1461824

Hom.:

Cov.:

AF XY:

0.000364

AC XY:

265

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000380

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000614

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000392

AC:

436

AN:

1111956

Other (OTH)

AF:

0.000281

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000250

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41528

American (AMR)

AF:

0.000327

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000382

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000276

Hom.:

Bravo

AF:

0.000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000255

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 522 of the LARS2 protein (p.Thr522Asn). This variant is present in population databases (rs199589947, gnomAD 0.05%). This missense change has been observed in individuals with Perrault syndrome (PMID: 23541342, 26970254, 28832386). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55871). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LARS2 protein function. Experimental studies have shown that this missense change affects LARS2 function (PMID: 23541342). For these reasons, this variant has been classified as Pathogenic. -

Mar 14, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 05, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect, with a 9 fold reduction in aminoacylation efficiency and complementation studies that found T522N results in partial rescue of LARS2 deficient yeast cells (PMID: 26537577, 23541342); 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: 28284481, 34440452, 32767731, 23541342, 24639874, 25506236, 26970254, 25254289, 28832386, 34426522, 31589614, 38186093, 34493867, 34997062, 34406847, 36450801, 35750896, 36693951, 26537577, 32423379, 29205794, 39052101) -

Nov 30, 2020

Genetic Services Laboratory, University of Chicago

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 26, 2020

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Perrault syndrome 4

Pathogenic:4

Feb 27, 2022

Reproductive Development, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

May 21, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A homozygous missense variant was identified, NM_015340.3(LARS2):c.1565C>A in exon 14 of 22 of the LARS2 gene. This substitution is predicted to create a minor amino acid change from a threonine to an asparagine at position 522 of the protein; NP_056155.1(LARS2):p.(Thr522Asn). The threonine at this position has very high conservation (100 vertebrates, UCSC), and is located within the catalytic domain (Demain, L. et al. (2017)). In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.03% (80 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic and segregated with disease in two families with Perrault syndrome (ClinVar, Pierce, S. et al. (2013), Demain, L. et al. (2017)). In addition, functional studies show that this variant is associated with a loss of efficiency of the protein (Riley, L. et al. (2016)). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -

Precision Medicine Center, Zhengzhou University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

This variant has been functionally studied, and has been found in multiple patients. -

Apr 04, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Perrault syndrome

Pathogenic:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Aug 06, 2018

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was identified in combination with a second variant in trans in the same gene (LARS2) in a patient with Perrault syndrome -

Inborn genetic diseases

Pathogenic:1

May 13, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1565C>A (p.T522N) alteration is located in exon 14 (coding exon 12) of the LARS2 gene. This alteration results from a C to A substitution at nucleotide position 1565, causing the threonine (T) at amino acid position 522 to be replaced by an asparagine (N). Based on data from gnomAD, the A allele has an overall frequency of 0.028% (80/282894) total alleles studied. The highest observed frequency was 0.049% (15/30616) of South Asian alleles. This variant has been identified in the homozygous state and/or in conjunction with other variant(s) in this same gene in individual(s) with features consistent with LARS2-related disease and segregated with disease in at least one family (Demain, 2017; Zerkaoui, 2017; Riley, 2015; Pierce, 2013). This amino acid position is highly conserved in available vertebrate species. In multiple assays testing LARS2 function, this variant showed functionally abnormal results (Pierce, 2013; Riley, 2015). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Perrault syndrome 4;C4310761:Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome

Pathogenic:1

Sep 27, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome

Pathogenic:1

Apr 04, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Rare genetic deafness

Pathogenic:1

Jan 02, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Thr522Asn variant in LARS2 has been reported in 3 individuals with Perraul t syndrome (Pierce 2013, Demain 2016). In two probands, the variant was homozygo us and segregated in three affected siblings, and the third proband was compound heterozygous for another missense variant, and both variants segregated in an a ffected sibling (Pierce 2013, Demain 2016). In vitro functional studies provide some evidence that the p.Thr522Asn variant may reduce the normal activity of the protein (Pierce 2013, Riley 2016). In addition, computational prediction tools and conservation analysis suggest a deleterious impact to the protein due to the p.Thr522Asn variant. This variant has been identified in several populations by the Genome Aggregation Database, including 48/126826 European chromosomes (gnom AD, http://gnomad.broadinstitute.org/; dbSNP rs199589947). However, its frequenc y is low enough to be consistent with a recessive carrier frequency. In summary, the p.Thr522Asn variant is pathogenic for autosomal recessive Perrault syndrome . -

LARS2-related disorder

Pathogenic:1

May 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The LARS2 c.1565C>A variant is predicted to result in the amino acid substitution p.Thr522Asn. This variant has been reported in the homozygous or compound heterozygous state in individuals with Perrault syndrome or hydrops, lactic acidosis, sideroblastic anemia, and multisystem failure (Pierce et al. 2013. PubMed ID: 23541342; Riley et al. 2015. PubMed ID: 26537577; Demain et al. 2016. PubMed ID: 26970254). This variant is reported in 0.049% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. -

LARS2-Related Disorders

Pathogenic:1

May 02, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LARS2 c.1565C>A (p.Thr522Asn) results in a non-conservative amino acid change located in the Aminoacyl-tRNA synthetase, class Ia (IPR002300) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 251490 control chromosomes. c.1565C>A has been reported in the literature in multiple individuals affected with LARS2-Related Disorders (Pierce_2013, Riley_2016, Demain_2017). These data indicate that the variant is very likely to 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: 26970254, 23541342, 26537577). ClinVar contains an entry for this variant (Variation ID: 55871). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.69

D;D;.;D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;.;D;.;D

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.71

D;D;D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Pathogenic

3.0

M;M;.;M;M

PhyloP100

7.5

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.8

D;D;D;.;.

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;D;D;.;.

Sift4G

Pathogenic

0.0

D;D;D;.;.

Polyphen

1.0

D;D;D;D;D

Vest4

0.90

MVP

0.95

MPC

0.89

ClinPred

0.84

GERP RS

5.5

Varity_R

0.87

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over