VCV001030526.6 - ClinVar

NM_002161.6(IARS1):c.3457T>C (p.Cys1153Arg)

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.

(5)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002161.6(IARS1):c.3457T>C (p.Cys1153Arg)

Variation ID: 1030526 Accession: VCV001030526.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q22.31 9: 92223442 (GRCh38) [ NCBI UCSC ] 9: 94985724 (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	Mar 22, 2021	Aug 18, 2024	May 2, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002161.6:c.3457T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002152.2:p.Cys1153Arg	missense
NM_001374299.1:c.3382T>C	NP_001361228.1:p.Cys1128Arg	missense
NM_001374300.1:c.3382T>C	NP_001361229.1:p.Cys1128Arg	missense
NM_001374301.1:c.3373T>C	NP_001361230.1:p.Cys1125Arg	missense
NM_001378569.1:c.3520T>C	NP_001365498.1:p.Cys1174Arg	missense
NM_001378571.1:c.3478T>C	NP_001365500.1:p.Cys1160Arg	missense
NM_001378572.1:c.3478T>C	NP_001365501.1:p.Cys1160Arg	missense
NM_001378573.1:c.3457T>C	NP_001365502.1:p.Cys1153Arg	missense
NM_001378574.1:c.3457T>C	NP_001365503.1:p.Cys1153Arg	missense
NM_001378575.1:c.3457T>C	NP_001365504.1:p.Cys1153Arg	missense
NM_001378576.1:c.3457T>C	NP_001365505.1:p.Cys1153Arg	missense
NM_001378577.1:c.3415T>C	NP_001365506.1:p.Cys1139Arg	missense
NM_001378578.1:c.3410-13T>C		intron variant
NM_001378579.1:c.3410-13T>C		intron variant
NM_001378580.1:c.3410-13T>C		intron variant
NM_001378582.1:c.3361T>C	NP_001365511.1:p.Cys1121Arg	missense
NM_001378583.1:c.3334T>C	NP_001365512.1:p.Cys1112Arg	missense
NM_001378584.1:c.3335-13T>C		intron variant
NM_001378585.1:c.3410-770T>C		intron variant
NM_001378586.1:c.3457T>C	NP_001365515.1:p.Cys1153Arg	missense
NM_013417.2:c.3457T>C
NM_013417.4:c.3457T>C	NP_038203.2:p.Cys1153Arg	missense
NR_073446.2:n.3394T>C		non-coding transcript variant
NC_000009.12:g.92223442A>G
NC_000009.11:g.94985724A>G
NG_051498.1:g.75315T>C

... more HGVS ... less HGVS

Protein change

C1139R, C1125R, C1121R, C1153R, C1160R, C1112R, C1128R, C1174R

Other names

Canonical SPDI

NC_000009.12:92223441:A:G

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.

0.00040 (G)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD) 0.00010

Trans-Omics for Precision Medicine (TOPMed) 0.00019

The Genome Aggregation Database (gnomAD), exomes 0.00032

Exome Aggregation Consortium (ExAC) 0.00035

1000 Genomes Project 0.00040

1000 Genomes Project 30x 0.00047

Links

dbSNP: rs141665010 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.
IARS1		-	-	GRCh38 GRCh38 GRCh37	352	392

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.
Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 27, 2021	RCV001332098.2
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Aug 17, 2022	RCV002546529.3
not specified	Uncertain significance (1)	criteria provided, single submitter	May 2, 2023	RCV004035728.1

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 (May 05, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001524301.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Aug 27, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002785988.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Aug 17, 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: SCV003271415.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Comment: This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1153 of the IARS protein … (more) This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1153 of the IARS protein (p.Cys1153Arg). This variant is present in population databases (rs141665010, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with IARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1030526). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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)
Uncertain significance (May 02, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003950773.2 First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024	Comment: The c.3457T>C (p.C1153R) alteration is located in exon 32 (coding exon 31) of the IARS gene. This alteration results from a T to C substitution … (more) The c.3457T>C (p.C1153R) alteration is located in exon 32 (coding exon 31) of the IARS gene. This alteration results from a T to C substitution at nucleotide position 3457, causing the cysteine (C) at amino acid position 1153 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005195458.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024

Comment:

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1153 of the IARS protein (p.Cys1153Arg). This variant is present in population databases (rs141665010, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with IARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1030526). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.

Comment:

The c.3457T>C (p.C1153R) alteration is located in exon 32 (coding exon 31) of the IARS gene. This alteration results from a T to C substitution at nucleotide position 3457, causing the cysteine (C) at amino acid position 1153 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs141665010 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_002161.6(IARS1):c.3457T>C (p.Cys1153Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs141665010 ...