chr3-45496316-C-A

Position:

chr3-45496316-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_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 (★★).

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:14O:1

Conservation

PhyloP100: 7.54

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 made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-45496316-C-A is Pathogenic according to our data. Variant chr3-45496316-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-45496316-C-A is described in Lovd as [Likely_pathogenic]. Variant chr3-45496316-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LARS2	NM_015340.4 linkuse as main transcript	c.1565C>A	p.Thr522Asn	missense_variant	14/22	ENST00000645846.2	NP_056155.1
LARS2-AS1	NR_048543.1 linkuse as main transcript	n.261-816G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LARS2	ENST00000645846.2 linkuse as main transcript	c.1565C>A	p.Thr522Asn	missense_variant	14/22		NM_015340.4	ENSP00000495093	P1
LARS2-AS1	ENST00000442534.2 linkuse as main transcript	n.261-816G>T		intron_variant, non_coding_transcript_variant		4

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

GnomAD3 exomes

AF:

0.000302

AC:

AN:

251490

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135918

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 SAS exome

AF:

0.000490

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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000614

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000392

Gnomad4 OTH exome

AF:

0.000281

GnomAD4 genome

AF:

0.000250

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000280

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:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	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). 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) has been performed at Invitae 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. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 05, 2024	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) -
Likely pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 14, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 26, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 30, 2020	- -

Perrault syndrome 4

Pathogenic:4

Pathogenic, no assertion criteria provided	research	Reproductive Development, Murdoch Childrens Research Institute	Feb 27, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 04, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	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. -
Pathogenic, criteria provided, single submitter	research	Precision Medicine Center, Zhengzhou University	-	This variant has been functionally studied, and has been found in multiple patients. -

Perrault syndrome

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Aug 06, 2018	This variant was identified in combination with a second variant in trans in the same gene (LARS2) in a patient with Perrault syndrome -

Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 04, 2013

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 02, 2017

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

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

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

May 02, 2024

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

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

MutationTaster

Benign

1.0

D;D;D

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

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