VCV002075981.2 - ClinVar

NM_020320.5(RARS2):c.16C>T (p.Arg6Cys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020320.5(RARS2):c.16C>T (p.Arg6Cys)

Variation ID: 2075981 Accession: VCV002075981.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q15 6: 87589942 (GRCh38) [ NCBI UCSC ] 6: 88299660 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Jun 17, 2024	Mar 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020320.5:c.16C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_064716.2:p.Arg6Cys	missense
NM_001318785.2:c.-675C>T		5 prime UTR
NM_001350505.2:c.16C>T	NP_001337434.1:p.Arg6Cys	missense
NM_001350506.2:c.-731C>T		5 prime UTR
NM_001350507.2:c.-854C>T		5 prime UTR
NM_001350508.2:c.-893C>T		5 prime UTR
NM_001350509.2:c.-601C>T		5 prime UTR
NM_001350510.2:c.-731C>T		5 prime UTR
NM_001350511.2:c.-850C>T		5 prime UTR
NR_134857.2:n.46C>T		non-coding transcript variant
NR_146738.2:n.46C>T		non-coding transcript variant
NR_146739.2:n.46C>T		non-coding transcript variant
NR_146740.2:n.46C>T		non-coding transcript variant
NR_146741.2:n.46C>T		non-coding transcript variant
NR_146742.2:n.46C>T		non-coding transcript variant
NR_146743.2:n.46C>T		non-coding transcript variant
NR_146744.2:n.46C>T		non-coding transcript variant
NR_146745.2:n.46C>T		non-coding transcript variant
NR_146746.2:n.46C>T		non-coding transcript variant
NR_146747.2:n.46C>T		non-coding transcript variant
NR_146748.2:n.46C>T		non-coding transcript variant
NR_146749.2:n.46C>T		non-coding transcript variant
NR_146750.2:n.46C>T		non-coding transcript variant
NR_146751.2:n.46C>T		non-coding transcript variant
NR_146752.2:n.46C>T		non-coding transcript variant
NR_146753.2:n.46C>T		non-coding transcript variant
NR_146754.2:n.46C>T		non-coding transcript variant
NR_146755.2:n.46C>T		non-coding transcript variant
NR_146756.2:n.46C>T		non-coding transcript variant
NR_146757.2:n.46C>T		non-coding transcript variant
NR_146758.2:n.46C>T		non-coding transcript variant
NR_146759.2:n.46C>T		non-coding transcript variant
NC_000006.12:g.87589942G>A
NC_000006.11:g.88299660G>A
NG_008601.1:g.5076C>T
NG_108712.1:g.926G>A

... more HGVS ... less HGVS

Protein change

R6C

Other names

Canonical SPDI

NC_000006.12:87589941:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RARS2		-	-	GRCh38 GRCh37	919	955

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (1)	criteria provided, single submitter	Apr 18, 2022	RCV002968067.2
Pontocerebellar hypoplasia type 6	Likely pathogenic (1)	criteria provided, single submitter	Mar 22, 2024	RCV004572492.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Apr 18, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003289911.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 30091983 Comment: This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 6 of the RARS2 protein … (more) This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 6 of the RARS2 protein (p.Arg6Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of pontocerebellar hypoplasia (PMID: 30091983). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RARS2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Likely pathogenic (Mar 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pontocerebellar hypoplasia type 6 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV005054085.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024

Comment:

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 6 of the RARS2 protein (p.Arg6Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of pontocerebellar hypoplasia (PMID: 30091983). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RARS2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Diagnostic value of partial exome sequencing in developmental disorders.	Gieldon L	PloS one	2018	PMID: 30091983

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_020320.5(RARS2):c.16C>T (p.Arg6Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...