NM_020320.5(RARS2):c.848T>A (p.Leu283Gln) AND Pontoneocerebellar hypoplasia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Aug 2, 2021
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:: RCV001553691.1

Allele description [Variation Report for NM_020320.5(RARS2):c.848T>A (p.Leu283Gln)]

NM_020320.5(RARS2):c.848T>A (p.Leu283Gln)

Gene:

RARS2:arginyl-tRNA synthetase 2, mitochondrial [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6q15

Genomic location:

Preferred name:

NM_020320.5(RARS2):c.848T>A (p.Leu283Gln)

HGVS:

NC_000006.12:g.87529572A>T
NG_008601.1:g.65446T>A
NM_001318785.2:c.323T>A
NM_001350505.2:c.848T>A
NM_001350506.2:c.323T>A
NM_001350507.2:c.323T>A
NM_001350508.2:c.323T>A
NM_001350509.2:c.323T>A
NM_001350510.2:c.323T>A
NM_001350511.2:c.323T>A
NM_020320.5:c.848T>AMANE SELECT
NP_001305714.1:p.Leu108Gln
NP_001337434.1:p.Leu283Gln
NP_001337435.1:p.Leu108Gln
NP_001337436.1:p.Leu108Gln
NP_001337437.1:p.Leu108Gln
NP_001337438.1:p.Leu108Gln
NP_001337439.1:p.Leu108Gln
NP_001337440.1:p.Leu108Gln
NP_064716.2:p.Leu283Gln
NC_000006.11:g.88239290A>T
NM_020320.3:c.848T>A
NM_020320.4:c.848T>A
NR_134857.2:n.878T>A
NR_146738.2:n.1146T>A
NR_146739.2:n.959T>A
NR_146740.2:n.1223T>A
NR_146741.2:n.885T>A
NR_146742.2:n.1261T>A
NR_146743.2:n.1099T>A
NR_146744.2:n.1223T>A
NR_146745.2:n.882T>A
NR_146746.2:n.1317T>A
NR_146747.2:n.661T>A
NR_146748.2:n.1099T>A
NR_146749.2:n.1099T>A
NR_146750.2:n.1223T>A
NR_146751.2:n.1099T>A
NR_146752.2:n.1167T>A
NR_146753.2:n.1015T>A
NR_146754.2:n.959T>A
NR_146755.2:n.1223T>A
NR_146756.2:n.878T>A
NR_146757.2:n.1149T>A
NR_146758.2:n.882T>A
NR_146759.2:n.882T>A

Protein change:

L108Q

Links:

dbSNP: rs1258569046

NCBI 1000 Genomes Browser:

rs1258569046

Molecular consequence:

NM_001318785.2:c.323T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350505.2:c.848T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350506.2:c.323T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350507.2:c.323T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350508.2:c.323T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350509.2:c.323T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350510.2:c.323T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350511.2:c.323T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020320.5:c.848T>A - missense variant - [Sequence Ontology: SO:0001583]
NR_134857.2:n.878T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146738.2:n.1146T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146739.2:n.959T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146740.2:n.1223T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146741.2:n.885T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146742.2:n.1261T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146743.2:n.1099T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146744.2:n.1223T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146745.2:n.882T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146746.2:n.1317T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146747.2:n.661T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146748.2:n.1099T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146749.2:n.1099T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146750.2:n.1223T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146751.2:n.1099T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146752.2:n.1167T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146753.2:n.1015T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146754.2:n.959T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146755.2:n.1223T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146756.2:n.878T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146757.2:n.1149T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146758.2:n.882T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146759.2:n.882T>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Functional consequence:

probably has functional consequence

Condition(s)

Name:: Pontoneocerebellar hypoplasia
Synonyms:: Pontocerebellar hypoplasia; Non-syndromic pontocerebellar hypoplasia
Identifiers:: MONDO: MONDO:0020135; MedGen: C1261175; Orphanet: 98523; OMIM: PS607596

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001774650	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 2, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29881806, 27061686 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001774650

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 2, 2021)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Expanding spectrum of RARS2 gene disorders: Myoclonic epilepsy, mental retardation, spasticity, and extrapyramidal features.

Mathew T, Avati A, D'Souza D, Therambil M.

Epilepsia Open. 2018 Jun;3(2):270-275. doi: 10.1002/epi4.12108.

PubMed [citation]

PMID:: 29881806
PMCID:: PMC5983106

RARS2 mutations in a sibship with infantile spasms.

Ngoh A, Bras J, Guerreiro R, Meyer E, McTague A, Dawson E, Mankad K, Gunny R, Clayton P, Mills PB, Thornton R, Lai M, Forsyth R, Kurian MA.

Epilepsia. 2016 May;57(5):e97-e102. doi: 10.1111/epi.13358. Epub 2016 Apr 8.

PubMed [citation]

PMID:: 27061686
PMCID:: PMC4864753

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001774650.1

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

Description

Variant summary: RARS2 c.848T>A (p.Leu283Gln) results in a non-conservative amino acid change located in the Arginyl-tRNA synthetase, catalytic core domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251248 control chromosomes. c.848T>A has been reported in the literature in multiple individuals affected with Pontocerebellar Hypoplasia, Type 6 or related diseases (e.g. Fitzgerald_2015, Ngoh_2016, Mathew_2018). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Feb 20, 2024

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