NM_002047.4(GARS1):c.1415A>G (p.His472Arg) AND Neuronopathy, distal hereditary motor, type 5A

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 25, 2018
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV000664213.6

Allele description [Variation Report for NM_002047.4(GARS1):c.1415A>G (p.His472Arg)]

NM_002047.4(GARS1):c.1415A>G (p.His472Arg)

Gene:

GARS1:glycyl-tRNA synthetase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p14.3

Genomic location:

Preferred name:

NM_002047.4(GARS1):c.1415A>G (p.His472Arg)

HGVS:

NC_000007.14:g.30621448A>G
NG_007942.1:g.31884A>G
NM_001316772.1:c.1253A>G
NM_002047.4:c.1415A>GMANE SELECT
NP_001303701.1:p.His418Arg
NP_002038.2:p.His472Arg
LRG_243t1:c.1415A>G
LRG_243:g.31884A>G
NC_000007.13:g.30661064A>G
NM_002047.1:c.1253A>G
NM_002047.2:c.1415A>G
NM_002047.3:c.1415A>G
p.His418Arg

Protein change:

H418R; HIS472ARG

Links:

OMIM: 600287.0013; dbSNP: rs1060502838

NCBI 1000 Genomes Browser:

rs1060502838

Molecular consequence:

NM_001316772.1:c.1253A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002047.4:c.1415A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Neuronopathy, distal hereditary motor, type 5A (HMND5)
Synonyms:: DHMN VA; NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 5; Distal Spinal Muscular Atrophy V
Identifiers:: MONDO: MONDO:0015353; MedGen: CN031873; Orphanet: 139536; OMIM: 600794

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000787774	Institute of Human Genetics, Cologne University	no assertion criteria provided	Pathogenic (Apr 25, 2018)	unknown	clinical testing
SCV001451405	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2014)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 31985473, 25168514

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000787774

Institute of Human Genetics, Cologne University

no assertion criteria provided

Pathogenic
(Apr 25, 2018)

unknown

clinical testing

SCV001451405

OMIM

no assertion criteria provided

Pathogenic
(Nov 1, 2014)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Clinical and Genetic Features in a Series of Eight Unrelated Patients with Neuropathy Due to Glycyl-tRNA Synthetase (GARS) Variants.

Forrester N, Rattihalli R, Horvath R, Maggi L, Manzur A, Fuller G, Gutowski N, Rankin J, Dick D, Buxton C, Greenslade M, Majumdar A.

J Neuromuscul Dis. 2020;7(2):137-143. doi: 10.3233/JND-200472.

PubMed [citation]

PMID:: 31985473

Impaired function is a common feature of neuropathy-associated glycyl-tRNA synthetase mutations.

Griffin LB, Sakaguchi R, McGuigan D, Gonzalez MA, Searby C, Züchner S, Hou YM, Antonellis A.

Hum Mutat. 2014 Nov;35(11):1363-71. doi: 10.1002/humu.22681.

PubMed [citation]

PMID:: 25168514
PMCID:: PMC4213347

Details of each submission

From Institute of Human Genetics, Cologne University, SCV000787774.1

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

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

From OMIM, SCV001451405.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 3 affected members of a large multigenerational family with autosomal dominant distal hereditary motor neuronopathy-5 (HMND5; 600794), Forrester et al. (2020) identified a heterozygous c.1415A-G transition (c.1415A-G, NM_002047.2) in the GARS1 gene, resulting in a his472-to-arg (H472R) substitution. An unrelated patient (patient 6) with the disorder also carried the mutation. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. Functional studies of the variant and studies of patient cells were not performed, but it was classified as pathogenic by ACMG criteria. Forrester et al. (2020) noted that Griffin et al. (2014) found that the H472R variant reduced aminoacyl-tRNA synthetase activity to 6.25% compared to wildtype.

#	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

Last Updated: Nov 3, 2024

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