ClinVar Miner

Submissions for variant NM_001040436.3(YARS2):c.156C>G (p.Phe52Leu)

dbSNP: rs267607180
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000292649 SCV000329675 pathogenic not provided 2020-07-10 criteria provided, single submitter clinical testing Functional studies have demonstrated that F52L results in reduced mitochondrial tRNATyr aminoacylation activity and reduces the affinity of the mutant protein for tRNATyr, leading to reduced mitochondrial protein synthesis (Riley et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20598274, 24344687, 23918765, 30026338)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000001111 SCV001164398 likely pathogenic Myopathy, lactic acidosis, and sideroblastic anemia 2 2018-12-03 criteria provided, single submitter research The homozygous p.Phe52Leu variant in YARS2 was identified by our study in one individual with myopathy, lactic acidosis, and sideroblastic anemia. The p.Phe52Leu variant in YARS2 has been reported in 9 Lebanese individuals with myopathy, lactic acidosis, and sideroblastic anemia, segregated with disease in 4 affected relatives from 2 families (PMID: 24344687, 20598274, 23918765, 30026338), and was been identified in 0.0008957% (1/111650) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs267607180). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported pathogenic in ClinVar (Variation ID: 1056). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that the p.Phe52Leu variant may impact protein function due to a deleterious effect on tRNATyr aminoacylation and mitochrondrial protein synthesis, which may explain the reduced levels of mitochondrial proteins in muscle cells from affected individuals (PMID: 20598274). However, these types of assays may not accurately represent biological function. In summary, although more studies are required to fully establish its clinical significance, the p.Phe52Leu variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP1_Moderate, PS3 (Richards 2015).
OMIM RCV000001111 SCV000021261 pathogenic Myopathy, lactic acidosis, and sideroblastic anemia 2 2013-12-17 no assertion criteria provided literature only

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