NM_020320.5(RARS2):c.773G>A (p.Arg258His) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Nov 12, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000727871.30

Allele description [Variation Report for NM_020320.5(RARS2):c.773G>A (p.Arg258His)]

NM_020320.5(RARS2):c.773G>A (p.Arg258His)

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.773G>A (p.Arg258His)

HGVS:

NC_000006.12:g.87529647C>T
NG_008601.1:g.65371G>A
NM_001318785.2:c.248G>A
NM_001350505.2:c.773G>A
NM_001350506.2:c.248G>A
NM_001350507.2:c.248G>A
NM_001350508.2:c.248G>A
NM_001350509.2:c.248G>A
NM_001350510.2:c.248G>A
NM_001350511.2:c.248G>A
NM_020320.5:c.773G>AMANE SELECT
NP_001305714.1:p.Arg83His
NP_001337434.1:p.Arg258His
NP_001337435.1:p.Arg83His
NP_001337436.1:p.Arg83His
NP_001337437.1:p.Arg83His
NP_001337438.1:p.Arg83His
NP_001337439.1:p.Arg83His
NP_001337440.1:p.Arg83His
NP_064716.2:p.Arg258His
NC_000006.11:g.88239365C>T
NM_020320.3:c.773G>A
NR_134857.2:n.803G>A
NR_146738.2:n.1071G>A
NR_146739.2:n.884G>A
NR_146740.2:n.1148G>A
NR_146741.2:n.810G>A
NR_146742.2:n.1186G>A
NR_146743.2:n.1024G>A
NR_146744.2:n.1148G>A
NR_146745.2:n.807G>A
NR_146746.2:n.1242G>A
NR_146747.2:n.586G>A
NR_146748.2:n.1024G>A
NR_146749.2:n.1024G>A
NR_146750.2:n.1148G>A
NR_146751.2:n.1024G>A
NR_146752.2:n.1092G>A
NR_146753.2:n.940G>A
NR_146754.2:n.884G>A
NR_146755.2:n.1148G>A
NR_146756.2:n.803G>A
NR_146757.2:n.1074G>A
NR_146758.2:n.807G>A
NR_146759.2:n.807G>A

Protein change:

R258H

Links:

dbSNP: rs145297855

NCBI 1000 Genomes Browser:

rs145297855

Molecular consequence:

NM_001318785.2:c.248G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350505.2:c.773G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350506.2:c.248G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350507.2:c.248G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350508.2:c.248G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350509.2:c.248G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350510.2:c.248G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001350511.2:c.248G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020320.5:c.773G>A - missense variant - [Sequence Ontology: SO:0001583]
NR_134857.2:n.803G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146738.2:n.1071G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146739.2:n.884G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146740.2:n.1148G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146741.2:n.810G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146742.2:n.1186G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146743.2:n.1024G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146744.2:n.1148G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146745.2:n.807G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146746.2:n.1242G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146747.2:n.586G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146748.2:n.1024G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146749.2:n.1024G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146750.2:n.1148G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146751.2:n.1024G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146752.2:n.1092G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146753.2:n.940G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146754.2:n.884G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146755.2:n.1148G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146756.2:n.803G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146757.2:n.1074G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146758.2:n.807G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_146759.2:n.807G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000252183	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Nov 12, 2024)	germline	clinical testing	Citation Link,
SCV000855363	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Jun 30, 2017)	germline	clinical testing	Citation Link,
SCV002497443	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Jan 1, 2023)	germline	clinical testing	Citation Link,
SCV002975713	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24047924, 33209735, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Subdural effusions and lack of early pontocerebellar hypoplasia in siblings with RARS2 mutations.

Kastrissianakis K, Anand G, Quaghebeur G, Price S, Prabhakar P, Marinova J, Brown G, McShane T.

Arch Dis Child. 2013 Dec;98(12):1004-7. doi: 10.1136/archdischild-2013-304308. Epub 2013 Sep 18.

PubMed [citation]

PMID:: 24047924

A term neonate with early myoclonic encephalopathy caused by RARS2 gene variants: a case report.

Xu Y, Wu BB, Wang HJ, Zhou SZ, Cheng GQ, Zhou YF.

Transl Pediatr. 2020 Oct;9(5):707-712. doi: 10.21037/tp-20-110.

PubMed [citation]

PMID:: 33209735
PMCID:: PMC7658767

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000252183.8

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

Description

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: 27061686, 29431110, 34717047, 33209735, 24047924)

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

From Eurofins Ntd Llc (ga), SCV000855363.1

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

From CeGaT Center for Human Genetics Tuebingen, SCV002497443.18

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

Description

RARS2: PM2, PM3, PP1, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002975713.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 258 of the RARS2 protein (p.Arg258His). This variant is present in population databases (rs145297855, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of RARS2-related conditions (PMID: 24047924, 33209735). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 215080). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: Nov 30, 2024

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