NM_002109.6(HARS1):c.410G>A (p.Arg137Gln) AND Autosomal dominant Charcot-Marie-Tooth disease type 2W

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 4, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000033152.9

Allele description [Variation Report for NM_002109.6(HARS1):c.410G>A (p.Arg137Gln)]

NM_002109.6(HARS1):c.410G>A (p.Arg137Gln)

Gene:

HARS1:histidyl-tRNA synthetase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q31.3

Genomic location:

Preferred name:

NM_002109.6(HARS1):c.410G>A (p.Arg137Gln)

Other names:

HARS1, ARG137GLN (rs191391414)

HGVS:

NC_000005.10:g.140679114C>T
NG_032158.1:g.17273G>A
NM_001258040.3:c.290G>A
NM_001258041.3:c.410G>A
NM_001258042.3:c.290G>A
NM_001289092.2:c.301-1099G>A
NM_001289093.2:c.181-1099G>A
NM_001289094.2:c.323G>A
NM_002109.6:c.410G>AMANE SELECT
NP_001244969.1:p.Arg97Gln
NP_001244970.1:p.Arg137Gln
NP_001244971.1:p.Arg97Gln
NP_001276023.1:p.Arg108Gln
NP_002100.2:p.Arg137Gln
LRG_1374t1:c.410G>A
LRG_1374:g.17273G>A
LRG_1374p1:p.Arg137Gln
NC_000005.9:g.140058699C>T
NM_001258041.1:c.410G>A
NM_002109.3:c.410G>A
NM_002109.5:c.410G>A
P12081:p.Arg137Gln

Protein change:

R108Q; ARG137GLN

Links:

UniProtKB: P12081#VAR_069022; OMIM: 142810.0002; dbSNP: rs191391414

NCBI 1000 Genomes Browser:

rs191391414

Molecular consequence:

NM_001289092.2:c.301-1099G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001289093.2:c.181-1099G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001258040.3:c.290G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258041.3:c.410G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258042.3:c.290G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001289094.2:c.323G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002109.6:c.410G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Autosomal dominant Charcot-Marie-Tooth disease type 2W
Synonyms:: CHARCOT-MARIE-TOOTH NEUROPATHY, TYPE 2W; CHARCOT-MARIE-TOOTH DISEASE, AXONAL, AUTOSOMAL DOMINANT, TYPE 2W; Charcot-Marie-Tooth disease, axonal, type 2w
Identifiers:: MONDO: MONDO:0014711; MedGen: C5567486; OMIM: 616625

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000537217	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha	criteria provided, single submitter (HA_assertions_20161101)	Uncertain significance (Jan 4, 2024)	unknown	research	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000537217

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha

criteria provided, single submitter

(HA_assertions_20161101)

Uncertain significance
(Jan 4, 2024)

unknown

research

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	1	not provided	not provided	1	not provided	research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

A loss-of-function variant in the human histidyl-tRNA synthetase (HARS) gene is neurotoxic in vivo.

Vester A, Velez-Ruiz G, McLaughlin HM; NISC Comparative Sequencing Program, Lupski JR, Talbot K, Vance JM, Züchner S, Roda RH, Fischbeck KH, Biesecker LG, Nicholson G, Beg AA, Antonellis A.

Hum Mutat. 2013 Jan;34(1):191-9. doi: 10.1002/humu.22210. Epub 2012 Oct 11.

PubMed [citation]

PMID:: 22930593
PMCID:: PMC3535524

Details of each submission

From OMIM, SCV000056934.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 64-year-old man with a 15-year history of impaired sensation in the lower extremities and electrophysiologic studies consistent with axonal Charcot-Marie-Tooth disease type 2W (CMT2W; 616625), Vester et al. (2013) identified a heterozygous 410G-A transition (rs191391414) in the HARS gene, resulting in an arg137-to-gln (R137Q) substitution at a highly conserved residue in the catalytic core of the enzyme. The patient was ascertained from a larger cohort of 363 individuals with peripheral neuropathy. The R137Q variant was also found in 3 of over 13,000 control chromosomes. One of the control carriers had no evidence of neuropathy at age 57 years. Generation of a yeast strain with deletion of the Hts1 gene (the ortholog of HARS) showed that the R137Q variant could not complement the Hts1 deletion, suggesting that it is a loss-of-function allele. Expression of the R137Q variant specifically in GABA motor nerves of C. elegans caused gross morphologic defects in commissural axons, with failure to reach the dorsal nerve cord, axonal beading, defasciculation, and breaks in the nerve cord. The animals with the variant also showed locomotor defects. Vester et al. (2013) concluded that the HARS R137Q variant may be a pathogenic allele that predisposes to the development of peripheral neuropathy, similar to other ARS mutations (see, e.g., GARS, 600287), but noted that a causal link remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology - CSER-HudsonAlpha, SCV000537217.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000056934	OMIM	flagged submission Reason: Claim with insufficient supporting evidence Notes: None	Pathogenic (Jan 1, 2013)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000056934

OMIM

flagged submission

Reason: Claim with insufficient supporting evidence

Notes: None

Pathogenic
(Jan 1, 2013)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Last Updated: May 16, 2025

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