rs138119149

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

Scores

9
10

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 0.555
Variant links:
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]
TMEM151B (HGNC:21315): (transmembrane protein 151B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

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
AARS2NM_020745.4 linkuse as main transcriptc.1774C>T p.Arg592Trp missense_variant 13/22 ENST00000244571.5 NP_065796.2 Q5JTZ9
AARS2XM_005249245.4 linkuse as main transcriptc.1483C>T p.Arg495Trp missense_variant 11/20 XP_005249302.1
POLR1CNM_001318876.2 linkuse as main transcriptc.946-137378G>A intron_variant NP_001305805.1 O15160-2
AARS2XR_007059282.1 linkuse as main transcriptn.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
AARS2ENST00000244571.5 linkuse as main transcriptc.1774C>T p.Arg592Trp missense_variant 13/221 NM_020745.4 ENSP00000244571.4 Q5JTZ9
ENSG00000272442ENST00000505802.1 linkuse as main transcriptn.313-2431G>A intron_variant 2 ENSP00000424257.1 H0Y9J4
TMEM151BENST00000438774.2 linkuse as main transcriptc.577-2431G>A intron_variant 3 ENSP00000409337.2 Q8IW70-2

Frequencies

GnomAD3 genomes
AF:
0.000237
AC:
36
AN:
152140
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00658
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000397
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000211
AC:
53
AN:
250804
Hom.:
0
AF XY:
0.000236
AC XY:
32
AN XY:
135564
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.000323
Gnomad NFE exome
AF:
0.000371
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000248
AC:
363
AN:
1461864
Hom.:
0
Cov.:
34
AF XY:
0.000256
AC XY:
186
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000765
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.000449
Gnomad4 NFE exome
AF:
0.000290
Gnomad4 OTH exome
AF:
0.000182
GnomAD4 genome
AF:
0.000237
AC:
36
AN:
152140
Hom.:
0
Cov.:
33
AF XY:
0.000229
AC XY:
17
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000397
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000288
Hom.:
0
Bravo
AF:
0.000204
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000272
AC:
33
EpiCase
AF:
0.000164
EpiControl
AF:
0.000356

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, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenSep 08, 2017- -
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 02, 2014- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 06, 2018The 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 submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMay 06, 2021Based 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 -
Pathogenic, criteria provided, single submitterclinical testing3billionMay 22, 2022The 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 submitterclinical testingInstitute of Human Genetics, Heidelberg UniversityDec 16, 2022- -
not provided Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 12, 2023This 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). -
Pathogenic, criteria provided, single submitterclinical testingGeneDxApr 19, 2023In 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 submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2024AARS2: PM3:Very Strong, PM2, BP4 -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 08, 2022- -
Leukoencephalopathy, progressive, with ovarian failure Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterMar 26, 2021Criteria applied: PM3_VSTR,PS3_SUP,PM2_SUP -
Pulmonary hypoplasia Pathogenic:1
Likely pathogenic, criteria provided, single submitterresearchPediatric Genomics Discovery Program, Yale UniversityFeb 04, 2019- -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 25, 2022The 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 (G&ouml;tz, 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Uncertain
-0.060
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.52
D
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.37
FATHMM_MKL
Benign
0.13
N
LIST_S2
Uncertain
0.91
D
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.34
T
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
0.81
L
PrimateAI
Benign
0.33
T
PROVEAN
Uncertain
-3.3
D
REVEL
Uncertain
0.47
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0040
D
Polyphen
0.99
D
Vest4
0.76
MVP
0.74
MPC
0.72
ClinPred
0.21
T
GERP RS
0.27
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.44
gMVP
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs138119149; hg19: chr6-44272249; COSMIC: COSV55118256; COSMIC: COSV55118256; API