VCV000008466.63 - ClinVar

NM_001605.3(AARS1):c.986G>A (p.Arg329His)

Germline

Classification

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.

(13)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001605.3(AARS1):c.986G>A (p.Arg329His)

Variation ID: 8466 Accession: VCV000008466.63

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q22.1 16: 70268356 (GRCh38) [ NCBI UCSC ] 16: 70302259 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Mar 29, 2015	Oct 20, 2024	Jan 17, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001605.3:c.986G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001596.2:p.Arg329His
NC_000016.10:g.70268356C>T
NC_000016.9:g.70302259C>T
NG_023191.1:g.26154G>A
LRG_359:g.26154G>A
LRG_359t1:c.986G>A	LRG_359p1:p.Arg329His
	P49588:p.Arg329His

... more HGVS ... less HGVS

Protein change

R329H

Other names

chr16:70268356C>T

Canonical SPDI

NC_000016.10:70268355:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA254396 UniProtKB: P49588#VAR_063527 OMIM: 601065.0001 dbSNP: rs267606621 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help 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 Help 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.
AARS1		No evidence available	No evidence available	GRCh38 GRCh37	1418	1464

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help 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 Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Charcot-Marie-Tooth disease axonal type 2N	Pathogenic (7)	criteria provided, multiple submitters, no conflicts	Dec 21, 2023	RCV000008987.13
Charcot-Marie-Tooth disease type 2	Pathogenic (1)	criteria provided, single submitter	Jan 17, 2024	RCV000168406.11
Charcot-Marie-Tooth disease	Pathogenic (1)	criteria provided, single submitter	-	RCV000192253.4
not provided	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 1, 2021	RCV001269580.25
AARS1-related disorder	Pathogenic (1)	no assertion criteria provided	Aug 21, 2024	RCV004730838.1

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 Help 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.
Pathogenic (Aug 18, 2015)	criteria provided, single submitter (Latour et al. (Am J Hum Genet. 2010)) Method: research	Charcot-Marie-Tooth disease axonal type 2N (Autosomal dominant inheritance) Affected status: yes Allele origin: paternal	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine Accession: SCV000292343.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (2) PubMed: 26257172‚ 20045102 Comment: This variant has been previously reported as disease-causing and was found in a proband and his father with axonal neuropathy Number of individuals with the variant: 2 Family history: yes
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease Affected status: yes Allele origin: germline	Molecular Genetics Laboratory, London Health Sciences Centre Accession: SCV001156510.1 First in ClinVar: Feb 09, 2020 Last updated: Feb 09, 2020
Likely pathogenic (Feb 21, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001449668.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1
Pathogenic (Apr 28, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001823215.1 First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021	Comment: 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 … (more) 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) (less)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease axonal type 2N Affected status: yes Allele origin: germline	Institute of Human Genetics, University Hospital of Duesseldorf Accession: SCV003803725.1 First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023
Pathogenic (Jan 17, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000219100.9 First in ClinVar: Mar 29, 2015 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 20045102‚ 22009580 Comment: 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). … (more) 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. (less)
Pathogenic (Dec 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Charcot-Marie-Tooth disease axonal type 2N Affected status: yes Allele origin: germline	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne Accession: SCV005016504.1 First in ClinVar: May 01, 2024 Last updated: May 01, 2024
Pathogenic (Jul 20, 2021)	criteria provided, single submitter (ACMG guidelines 2015) Method: research	Charcot-Marie-Tooth disease axonal type 2N (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Laboratório de Neurologia Aplicada e Experimental, Faculdade de Medicina de Ribeirao Preto – Universidade de Sao Paulo Accession: SCV001933036.1 First in ClinVar: Mar 28, 2022 Last updated: Mar 28, 2022	Publications: PubMed (4) PubMed: 26032230‚ 20045102‚ 22009580‚ 32314272 Comment: 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 … (more) 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. (less) Age: 0-9 years Sex: male Geographic origin: Brazil
Pathogenic (Nov 01, 2021)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV002063523.20 First in ClinVar: Jan 29, 2022 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (Jan 01, 2012)	no assertion criteria provided Method: literature only	CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2N Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029201.3 First in ClinVar: Apr 04, 2013 Last updated: Nov 02, 2019	Publications: PubMed (2) PubMed: 20045102‚ 22009580 Comment on evidence: In affected members of 2 unrelated French families with autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N; 613287), Latour et al. (2010) identified a heterozygous 986G-A … (more) In affected members of 2 unrelated French families with autosomal dominant Charcot-Marie-Tooth disease type 2N (CMT2N; 613287), Latour et al. (2010) identified a heterozygous 986G-A transition in exon 8 of the AARS gene, resulting in an arg329-to-his (R329H) substitution in the alpha-10 helix. This highly conserved residue is the ortholog of R314 in E. coli, which is 1 of the major determinants for binding and efficient aminoacylation of tRNAs. E. coli mutants in this residue showed significant reduction in enzyme activity due to reduced binding, but the authors also postulated that the mutation could result in qualitative errors and the binding of noncognate tRNAs. The R329H mutation was not found in 1,000 control chromosomes. Haplotype analysis excluded a founder effect. McLaughlin et al. (2012) identified a heterozygous R329H mutation in affected members of an Australian family with CMT2N. The substitution occurs within a highly conserved residue in the tRNA-binding domain. Aminoacylation studies showed that the mutation reduced enzyme activity by about 50% and was unable to complement deletion in yeast viability studies. There did not appear to be a dominant-negative effect. Haplotype analysis of this family and the 2 reported by Latour et al. (2010) showed that the mutation occurred independently. Bisulfite sequencing indicated that the mutation occurred via methylation-mediated deamination of a CpG dinucleotide on the noncoding strand. The findings indicated that R329H is a recurrent loss-of-function mutation. (less)
Uncertain significance (Jan 06, 2016)	no assertion criteria provided Method: literature only	Charcot-Marie-Tooth disease axonal type 2N Affected status: yes Allele origin: germline	Inherited Neuropathy Consortium Ii, University Of Miami Accession: SCV004011917.1 First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023	Publications: PubMed (1) PubMed: 21208200
Pathogenic (Aug 21, 2024)	no assertion criteria provided Method: clinical testing	AARS1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005339311.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: 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 … (more) 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. (less)
Pathogenic (-)	no assertion criteria provided (ACGS Guidelines, 2016) Method: clinical testing	Charcot-Marie-Tooth disease axonal type 2N Affected status: yes Allele origin: germline	Genomics England Pilot Project, Genomics England Accession: SCV001760376.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021
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Comment:

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)

Comment:

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.

Comment:

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.

Comment:

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.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Alanyl-tRNA synthetase 1 (AARS1) gene mutation in a family with intermediate Charcot-Marie-Tooth neuropathy.	Lee AJ	Genes & genomics	2020	PMID: 32314272
Exome Sequence Analysis Suggests that Genetic Burden Contributes to Phenotypic Variability and Complex Neuropathy.	Gonzaga-Jauregui C	Cell reports	2015	PMID: 26257172
Genotype/phenotype correlations in AARS-related neuropathy in a cohort of patients from the United Kingdom and Ireland.	Bansagi B	Journal of neurology	2015	PMID: 26032230
A recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with Charcot-Marie-Tooth disease type 2N (CMT2N).	McLaughlin HM	Human mutation	2012	PMID: 22009580
Twenty-five novel mutations including duplications in the ATP7A gene.	Moizard MP	Clinical genetics	2011	PMID: 21208200
A major determinant for binding and aminoacylation of tRNA(Ala) in cytoplasmic Alanyl-tRNA synthetase is mutated in dominant axonal Charcot-Marie-Tooth disease.	Latour P	American journal of human genetics	2010	PMID: 20045102

Text-mined citations for rs267606621 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001605.3(AARS1):c.986G>A (p.Arg329His)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs267606621 ...