Submissions for variant NM_015340.4(LARS2):c.1565C>A (p.Thr522Asn)

gnomAD frequency: 0.00025  dbSNP: rs199589947

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520936	SCV000617777	pathogenic	not provided	2024-09-05	criteria provided, single submitter	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)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000604453	SCV000711536	pathogenic	Rare genetic deafness	2017-01-02	criteria provided, single submitter	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 .
Center of Genomic medicine, Geneva, University Hospital of Geneva	RCV000857234	SCV000999821	pathogenic	Perrault syndrome	2018-08-06	criteria provided, single submitter	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
Revvity Omics, Revvity	RCV000520936	SCV002022653	likely pathogenic	not provided	2020-03-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000520936	SCV002064436	likely pathogenic	not provided	2020-11-30	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000049285	SCV002769218	pathogenic	Perrault syndrome 4	2020-05-21	criteria provided, single submitter	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000520936	SCV003525214	pathogenic	not provided	2023-12-31	criteria provided, single submitter	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). 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.
Precision Medicine Center, Zhengzhou University	RCV000049285	SCV003845948	pathogenic	Perrault syndrome 4		criteria provided, single submitter	research	This variant has been functionally studied, and has been found in multiple patients.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689437	SCV005186031	pathogenic	LARS2-Related Disorders	2024-05-02	criteria provided, single submitter	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.
OMIM	RCV000049285	SCV000077543	pathogenic	Perrault syndrome 4	2013-04-04	no assertion criteria provided	literature only
OMIM	RCV000235552	SCV000292565	pathogenic	Hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome	2013-04-04	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000520936	SCV000802355	likely pathogenic	not provided	2016-03-14	no assertion criteria provided	clinical testing
Reproductive Development, Murdoch Childrens Research Institute	RCV000049285	SCV002099519	pathogenic	Perrault syndrome 4	2022-02-27	no assertion criteria provided	research
GeneReviews	RCV000857234	SCV003525956	not provided	Perrault syndrome		no assertion provided	literature only
PreventionGenetics, part of Exact Sciences	RCV004730866	SCV005336405	pathogenic	LARS2-related disorder	2024-05-07	no assertion criteria provided	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.