rs267606621

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_ModeratePM1PM2PP3_StrongPP5_Very_Strong

The NM_001605.3(AARS1):​c.986G>A​(p.Arg329His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

AARS1
NM_001605.3 missense

Scores

18
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12U:1

Conservation

PhyloP100: 7.91
Variant links:
Genes affected
AARS1 (HGNC:20): (alanyl-tRNA synthetase 1) The human alanyl-tRNA synthetase (AARS) belongs to a family of tRNA synthases, of the class II enzymes. Class II tRNA synthases evolved early in evolution and are highly conserved. This is reflected by the fact that 498 of the 968-residue polypeptide human AARS shares 41% identity witht the E.coli protein. tRNA synthases are the enzymes that interpret the RNA code and attach specific aminoacids to the tRNAs that contain the cognate trinucleotide anticodons. They consist of a catalytic domain which interacts with the amino acid acceptor-T psi C helix of the tRNA, and a second domain which interacts with the rest of the tRNA structure. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PS1
Transcript NM_001605.3 (AARS1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a helix (size 20) in uniprot entity SYAC_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001605.3
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 16-70268356-C-T is Pathogenic according to our data. Variant chr16-70268356-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-70268356-C-T is described in Lovd as [Pathogenic]. Variant chr16-70268356-C-T is described in Lovd as [Likely_pathogenic]. Variant chr16-70268356-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AARS1NM_001605.3 linkc.986G>A p.Arg329His missense_variant Exon 8 of 21 ENST00000261772.13 NP_001596.2 P49588-1
AARS1XM_047433666.1 linkc.986G>A p.Arg329His missense_variant Exon 8 of 16 XP_047289622.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AARS1ENST00000261772.13 linkc.986G>A p.Arg329His missense_variant Exon 8 of 21 1 NM_001605.3 ENSP00000261772.8 P49588-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461816
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2N Pathogenic:6Uncertain:1
-
Genomics England Pilot Project, Genomics England
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 18, 2015
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

This variant has been previously reported as disease-causing and was found in a proband and his father with axonal neuropathy -

Jul 20, 2021
Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

The p.Arg329His variant in AARS1 has been reported in several families worldwide with Charcot-Marie-Tooth's autosomal dominant axonal form (PMID:26032230; 20045102; 22009580; 32314272). This variant is not present in population databases (GnomAD and AbraOM). ClinVar contains an entry for this variant (Variation ID: 8466). In summary, the Arg329His meets our criteria to be classified as pathogenic. -

Jan 01, 2012
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

-
Institute of Human Genetics, University Hospital of Duesseldorf
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 06, 2016
Inherited Neuropathy Consortium Ii, University Of Miami
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Dec 21, 2023
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:3
Nov 01, 2021
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 12, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on enzyme activity (PMID: 22009580); Not observed at significant frequency in large population cohorts (gnomAD); 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: 27549087, 31775912, 25476837, 22009580, 28251916, 30373780, 26257172, 20301462, 24088041, 23806086, 30569560, 31701603, 30643024, 32376792, 32314272, 25817015, 34758253, 37273706, 33726816, 36738734, 20045102, 34813128) -

Feb 21, 2017
Clinical Genetics and Genomics, Karolinska University Hospital
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease Pathogenic:1
-
Molecular Genetics Laboratory, London Health Sciences Centre
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease type 2 Pathogenic:1
Nov 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 329 of the AARS protein (p.Arg329His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant Charcot-Marie-Tooth disease (PMID: 20045102, 22009580). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8466). 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 AARS protein function. Experimental studies have shown that this missense change affects AARS function (PMID: 22009580). For these reasons, this variant has been classified as Pathogenic. -

AARS1-related disorder Pathogenic:1
Aug 21, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The AARS1 c.986G>A variant is predicted to result in the amino acid substitution p.Arg329His. This variant has been reported in several individuals with Charcot-Marie-Tooth disease and has been demonstrated to segregate with disease in at least three families with Charcot-Marie-Tooth disease (Latour et al. 2010. PubMed ID: 20045102; McLaughlin et al. 2011. PubMed ID: 22009580; Bansagi et al. 2017. PubMed ID: 28251916; Bacquet et al. 2018. PubMed ID: 30373780; Table S2, Volodarsky et al. 2020. PubMed ID: 32376792). In vitro functional analysis demonstrated that expression of this variant results in severely impaired enzyme activity with an ~50-fold decrease in catalytic efficiency compared to wild-type (McLaughlin et al. 2011. PubMed ID: 22009580). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been consistently interpreted as pathogenic by multiple laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/8466/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.94
D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.99
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.46
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.3
H
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-4.9
D
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0010
D
Polyphen
1.0
D
Vest4
0.91
MutPred
0.98
Loss of methylation at R329 (P = 0.119);
MVP
0.98
MPC
0.75
ClinPred
1.0
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.91
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs267606621; hg19: chr16-70302259; COSMIC: COSV55746130; COSMIC: COSV55746130; API