16-70268356-C-T

Variant names:

• chr16-70268356-C-T
• rs267606621
• NM_001605.3:c.986G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R329C) has been classified as Likely pathogenic.

• 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
• Publications: 44 publications found

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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease axonal type 2N

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• developmental and epileptic encephalopathy, 29

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• trichothiodystrophy 8, nonphotosensitive

  Inheritance: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_001605.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-70268357-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 422259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 8466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AARS1	NM_001605.3	c.986G>A	p.Arg329His	missense_variant	Exon 8 of 21	ENST00000261772.13	NP_001596.2
AARS1	XM_047433666.1	c.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
AARS1	ENST00000261772.13	c.986G>A	p.Arg329His	missense_variant	Exon 8 of 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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111964

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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

-

Institute of Human Genetics, University Hospital of Duesseldorf

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

Dec 21, 2023

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

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 -

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:3

Feb 21, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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) -

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
PhyloP100		7.9
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
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

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