rs138119149
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_020745.4(AARS2):c.1774C>T(p.Arg592Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000247 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00025 ( 0 hom. )
Consequence
AARS2
NM_020745.4 missense
NM_020745.4 missense
Scores
9
10
Clinical Significance
Conservation
PhyloP100: 0.555
Genes affected
AARS2 (HGNC:21022): (alanyl-tRNA synthetase 2, mitochondrial) The protein encoded by this gene belongs to the class-II aminoacyl-tRNA synthetase family. Aminoacyl-tRNA synthetases play critical roles in mRNA translation by charging tRNAs with their cognate amino acids. The encoded protein is a mitochondrial enzyme that specifically aminoacylates alanyl-tRNA. Mutations in this gene are a cause of combined oxidative phosphorylation deficiency 8. [provided by RefSeq, Dec 2011]
POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-44304512-G-A is Pathogenic according to our data. Variant chr6-44304512-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-44304512-G-A is described in Lovd as [Pathogenic]. Variant chr6-44304512-G-A is described in Lovd as [Likely_pathogenic]. Variant chr6-44304512-G-A is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.33908463). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| AARS2 | NM_020745.4 | c.1774C>T | p.Arg592Trp | missense_variant | 13/22 | ENST00000244571.5 | NP_065796.2 | |
| AARS2 | XM_005249245.4 | c.1483C>T | p.Arg495Trp | missense_variant | 11/20 | XP_005249302.1 | ||
| POLR1C | NM_001318876.2 | c.946-137378G>A | intron_variant | NP_001305805.1 | ||||
| AARS2 | XR_007059282.1 | n.1779C>T | splice_region_variant, non_coding_transcript_exon_variant | 13/14 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| AARS2 | ENST00000244571.5 | c.1774C>T | p.Arg592Trp | missense_variant | 13/22 | 1 | NM_020745.4 | ENSP00000244571.4 | ||
| ENSG00000272442 | ENST00000505802.1 | n.313-2431G>A | intron_variant | 2 | ENSP00000424257.1 | |||||
| TMEM151B | ENST00000438774.2 | c.577-2431G>A | intron_variant | 3 | ENSP00000409337.2 |
Frequencies
GnomAD3 genomes 0.000237 AC: 36AN: 152140Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000211 AC: 53AN: 250804Hom.: 0 AF XY: 0.000236 AC XY: 32AN XY: 135564
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GnomAD4 exome AF: 0.000248 AC: 363AN: 1461864Hom.: 0 Cov.: 34 AF XY: 0.000256 AC XY: 186AN XY: 727228
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GnomAD4 genome 0.000237 AC: 36AN: 152140Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17AN XY: 74308
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Combined oxidative phosphorylation defect type 8 Pathogenic:6
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 02, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Sep 08, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 06, 2018 | The p.Arg592Trp variant in AARS2 has been reported in the homozygous or in the c ompound heterozygous state with loss-of-function or rare missense variants in 12 individuals with combined oxidative phosphorylation deficiency 8 with severe hy pertrophic cardiomyopathy, and segregated with disease in 1 affected family memb er (Gotz 2011, Calvo 2012, Taylor 2014, Euro 2015, Mazurova 2017, Kamps 2018). I t also segregated with disease in the affected twin siblings of two of the proba nds; however, it was not specified if these were identical or fraternal twins (E uro 2015, Kamps 2018). It has also been identified in 0.04% (48/126154) of Europ ean chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadi nstitute.org). Although this variant has been seen in the general population, it s frequency is low enough to be consistent with a recessive carrier frequency. C omputational prediction tools and conservation analysis do not provide strong su pport for or against an impact to the protein, though structural modeling sugges ts this variant may have an impact on protein function (Euro 2015). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessi ve combined oxidative phosphorylation deficiency 8 based on case observations, s egregation studies, and predicted impact on protein. ACMG/AMP criteria applied: ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PP1. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Heidelberg University | Dec 16, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000030940). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:21549344, 22277967, 25058219, 25705216, 29440775). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 25058219, 25705216, 29440775). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with combined oxidative phosphorylation deficiency 8 (MIM#614096) and leukoencephalopathy, progressive, with ovarian failure (MIM#615889) (PMIDs: 28633377, 30285085, 24808023). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (64 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (p.R592Q: 4 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated editing domain (PMID: 25705216). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is a recurrent founder mutation and has been reported as homozygous or compound heterozygous in multiple individuals with severe infantile cardiomyopathy (PMIDs: 21549344, 25058219, 25705216). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Cytochrome c oxidase (COX) activity was severely reduced in heart and skeletal muscles of a deceased patient homozygous for the p.R592W variant. Blue-native electrophoresis of mitochondrial respiratory chain complexes demonstrated severely reduced COX and complex I (CI) in the heart, severe COX deficiency and CI reduction in the brain, and partial complex III deficiency in both tissues (PMID: 21549344). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_020745.3:c.647dupG ; p.Cys218Leufs*6) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2023 | 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: 25058219, 27251004, 27839525, 28822227, 21549344, 22277967, 24808023, 25705216, 29440775, 30952159, 31980526, 30819764, 31589614, 32938192, 33726816, 34088003) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | AARS2: PM3:Very Strong, PM2, BP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 08, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 12, 2023 | This missense change is located in the editing domain of mitochondrial alanyl-tRNA synthetase and structural modeling suggests that this variant severely compromises aminoacylation activity (PMID: 25705216, 21549344, 25058219, 22277967). ClinVar contains an entry for this variant (Variation ID: 30940). 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) performed at Invitae indicates that this missense variant is expected to disrupt AARS2 protein function. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individuals with infantile mitochondrial cardiomyopathy with combined oxidative phosphorylation deficiency (PMID: 21549344, 22277967, 25058219, 25705216). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs138119149, gnomAD 0.04%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 592 of the AARS2 protein (p.Arg592Trp). - |
Leukoencephalopathy, progressive, with ovarian failure Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 26, 2021 | Criteria applied: PM3_VSTR,PS3_SUP,PM2_SUP - |
Pulmonary hypoplasia Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | research | Pediatric Genomics Discovery Program, Yale University | Feb 04, 2019 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 25, 2022 | The c.1774C>T (p.R592W) alteration is located in exon 13 of the AARS2 gene. This alteration results from a C to T substitution at nucleotide position 1774, causing the arginine (R) at amino acid position 592 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.02% (64/282172) total alleles studied. The highest observed frequency was 0.04% (52/128596) of European (non-Finnish) alleles. This alteration is a recurrent pathogenic mutation reported in multiple unrelated patients and several siblings with a severe infantile mitochondrial hypertrophic cardiomyopathy phenotype (Götz, 2011; Taylor, 2014; Kamps, 2018). This amino acid position is not well conserved in available vertebrate species. The p.R592 amino acid is located in the editing domain of mtAlaRS. Protein modeling studies suggest that this residue is surface exposed and that may be involved in specific recognition and/or binding of mischarged mitochondrial tRNAAla in the editing domain (Gotz, 2011). Structural analysis predicts that this alteration will reduce the aminoacylation activity of the synthetase, because all mtAlaRS domains contribute to tRNA binding for aminoacylation (Euro, 2015). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at