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
Consequence
NM_015340.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000250 AC: 38AN: 152142Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000302 AC: 76AN: 251490Hom.: 0 AF XY: 0.000258 AC XY: 35AN XY: 135918
GnomAD4 exome AF: 0.000358 AC: 524AN: 1461824Hom.: 0 Cov.: 30 AF XY: 0.000364 AC XY: 265AN XY: 727230
GnomAD4 genome AF: 0.000250 AC: 38AN: 152260Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74440
ClinVar
Submissions by phenotype
not provided Pathogenic:5
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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. -
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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) -
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Perrault syndrome 4 Pathogenic:4
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This variant has been functionally studied, and has been found in multiple patients. -
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. -
Perrault syndrome Pathogenic:1Other:1
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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
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Rare genetic deafness Pathogenic:1
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 Disorders Pathogenic:1
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. -
LARS2-related disorder Pathogenic:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at