rs267606621

Positions:

• chr16-70268356-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5_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 same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AARS1 NM_001605.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 U:1
• Conservation: PhyloP100: 7.91

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]

AARS1 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
AARS1	NM_001605.3	c.986G>A	p.Arg329His	missense_variant	8/21	ENST00000261772.13	NP_001596.2
AARS1	XM_047433666.1	c.986G>A	p.Arg329His	missense_variant	8/16		XP_047289622.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AARS1	ENST00000261772.13	c.986G>A	p.Arg329His	missense_variant	8/21	1	NM_001605.3	ENSP00000261772.8

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

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:12 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2N Pathogenic:6 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2012	- -
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, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
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, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Dec 21, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Uncertain significance, no assertion criteria provided	literature only	Inherited Neuropathy Consortium Ii, University Of Miami	Jan 06, 2016	- -

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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2024	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) -

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

Labcorp Genetics (formerly Invitae), Labcorp

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. -

AARS1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 21, 2024

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

Other links and lift over

dbSNP: rs267606621; hg19: chr16-70302259; COSMIC: COSV55746130; COSMIC: COSV55746130;