ClinVar Genomic variation as it relates to human health
NM_001040436.3(YARS2):c.156C>G (p.Phe52Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001040436.3(YARS2):c.156C>G (p.Phe52Leu)
Variation ID: 1056 Accession: VCV000001056.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p11.21 12: 32755719 (GRCh38) [ NCBI UCSC ] 12: 32908653 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 Jul 25, 2020 Jul 10, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001040436.3:c.156C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001035526.1:p.Phe52Leu missense NC_000012.12:g.32755719G>C NC_000012.11:g.32908653G>C NG_028122.1:g.5235C>G Q9Y2Z4:p.Phe52Leu - Protein change
- F52L
- Other names
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- Canonical SPDI
- NC_000012.12:32755718:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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YARS2 | - | - |
GRCh38 GRCh37 |
253 | 315 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (2) |
criteria provided, single submitter
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Dec 3, 2018 | RCV000001111.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2020 | RCV000292649.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Dec 03, 2018)
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criteria provided, single submitter
Method: research
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Myopathy, lactic acidosis, and sideroblastic anemia 2
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001164398.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Jul 10, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000329675.6
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(Dec 17, 2013)
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no assertion criteria provided
Method: literature only
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MYOPATHY, LACTIC ACIDOSIS, AND SIDEROBLASTIC ANEMIA 2
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021261.4
First in ClinVar: Apr 04, 2013 Last updated: Jul 25, 2020 |
Comment on evidence:
In 3 patients from 2 consanguineous Lebanese families with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia-2 (MLASA2; 613561), Riley et al. (2010) identified a homozygous … (more)
In 3 patients from 2 consanguineous Lebanese families with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia-2 (MLASA2; 613561), Riley et al. (2010) identified a homozygous 156C-G transversion in the YARS2 gene, resulting in a phe52-to-leu (F52L) substitution in a conserved region of the catalytic domain. Haplotype analysis suggested a founder effect, but the mutation was not observed in 220 control chromosomes, including 104 of Lebanese origin. Immunoblot analysis of patient skeletal muscle showed slightly reduced levels of YARS2, as well as reduced levels of mitochondrial-encoded protein subunits of respiratory chain complexes, indicating a reduction in mitochondrial protein synthesis. In vitro functional expression assays showed that the mutant YARS2 protein had a 2-fold reduction in catalytic activity and a reduction in affinity for tRNA-tyr, resulting in an overall 9-fold loss of catalytic efficiency. The findings indicated that the mutation resulted in reduced aminoacylation efficiency, causing a defect in mitochondrial protein synthesis with a subsequent impairment of mitochondrial respiratory activity. In another Lebanese patient with MLASA2, Shahni et al. (2013) identified homozygosity for the F52L mutation in the YARS2 gene. The patient's parents, who were not known to be related, were heterozygous for the mutation, lending support to the hypothesis that F52L is a Lebanese founder mutation. Riley et al. (2013) identified a homozygous P52L mutation in a female infant of Lebanese origin with a severe form of MLASA2 resulting in death at age 3 months from cardiorespiratory failure. She presented at age 8 weeks in hypotensive shock after an infectious illness and was found to have left ventricular hypertrophy, hepatomegaly with raised transaminases and coagulopathy, lactic acidosis, and sideroblastic anemia. An unrelated patient of Lebanese origin with a much less severe phenotype was also found to be homozygous for the P52L mutation. This patient was found to have sideroblastic anemia at age 23 years. She also had scoliosis and a mild restrictive pulmonary defect, but no other abnormalities. Riley et al. (2013) emphasized the wide phenotypic spectrum associated with the P42L mutation and postulated that the differences may be due to different mitochondrial haplogroups: these 2 patients had haplogroup T and H, respectively, and the patients reported by Riley et al. (2010) were of haplogroup K. Myotubes derived from fibroblasts of 1 of the patients reported by Riley et al. (2010) showed a more severe defect in respiratory chain activity than fibroblasts, suggesting increased demand for this enzyme in muscle tissue. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2. | Riley LG | Haematologica | 2018 | PMID: 30026338 |
Phenotypic variability and identification of novel YARS2 mutations in YARS2 mitochondrial myopathy, lactic acidosis and sideroblastic anaemia. | Riley LG | Orphanet journal of rare diseases | 2013 | PMID: 24344687 |
A distinct mitochondrial myopathy, lactic acidosis and sideroblastic anemia (MLASA) phenotype associates with YARS2 mutations. | Shahni R | American journal of medical genetics. Part A | 2013 | PMID: 23918765 |
Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome. | Riley LG | American journal of human genetics | 2010 | PMID: 20598274 |
Text-mined citations for rs267607180 ...
HelpRecord last updated Mar 30, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.