rs267606621
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_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. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R329C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001605.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AARS1 | NM_001605.3 | c.986G>A | p.Arg329His | missense_variant | 8/21 | ENST00000261772.13 | |
AARS1 | XM_047433666.1 | c.986G>A | p.Arg329His | missense_variant | 8/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AARS1 | ENST00000261772.13 | c.986G>A | p.Arg329His | missense_variant | 8/21 | 1 | NM_001605.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461816Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727212
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2N Pathogenic:6Uncertain:1
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium Ii, University Of Miami | Jan 06, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Dec 21, 2023 | - - |
Pathogenic, criteria provided, single submitter | research | Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo | Jul 20, 2021 | 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. - |
Pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Aug 18, 2015 | This variant has been previously reported as disease-causing and was found in a proband and his father with axonal neuropathy - |
Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital of Duesseldorf | - | - - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Feb 21, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 28, 2020 | Published functional studies demonstrate a damaging effect on enzyme activity (McLaughlin et al., 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32376792, 32314272, 30643024, 31701603, 30569560, 23806086, 24088041, 20301462, 26257172, 30373780, 28251916, 25476837, 22009580, 20045102, 27549087, 31775912) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2021 | - - |
Charcot-Marie-Tooth disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Charcot-Marie-Tooth disease type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | 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). 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) has been performed at Invitae 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at