VCV000155733.58 - ClinVar

NM_001605.3(AARS1):c.1685C>T (p.Thr562Ile)

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.

(14)

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.

Benign/Likely benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001605.3(AARS1):c.1685C>T (p.Thr562Ile)

Variation ID: 155733 Accession: VCV000155733.58

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q22.1 16: 70261144 (GRCh38) [ NCBI UCSC ] 16: 70295047 (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	Sep 4, 2014	Oct 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001605.3:c.1685C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001596.2:p.Thr562Ile	missense
NC_000016.10:g.70261144G>A
NC_000016.9:g.70295047G>A
NG_023191.1:g.33366C>T
LRG_359:g.33366C>T
LRG_359t1:c.1685C>T	LRG_359p1:p.Thr562Ile

... more HGVS ... less HGVS

Protein change

T562I

Other names

Canonical SPDI

NC_000016.10:70261143: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.

0.00339 (A)

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

1000 Genomes Project 30x 0.00328

1000 Genomes Project 0.00339

Exome Aggregation Consortium (ExAC) 0.00531

The Genome Aggregation Database (gnomAD), exomes 0.00540

Trans-Omics for Precision Medicine (TOPMed) 0.00564

The Genome Aggregation Database (gnomAD) 0.00591

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00631

Links

ClinGen: CA233062 dbSNP: rs148355156 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.
AARS1		No evidence available	No evidence available	GRCh38 GRCh37	1420	1466

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	Benign/Likely benign (7)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000143803.39
Charcot-Marie-Tooth disease type 2	Benign (1)	criteria provided, single submitter	Jan 31, 2024	RCV000204958.16
Charcot-Marie-Tooth disease axonal type 2N	Benign/Likely benign (4)	criteria provided, multiple submitters, no conflicts	May 28, 2019	RCV000509259.7
not specified	Likely benign (2)	criteria provided, single submitter	Mar 6, 2017	RCV000736083.16

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.
Likely benign (Apr 06, 2016)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Charcot-Marie-Tooth disease axonal type 2N Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000743758.1 First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001833236.1 First in ClinVar: Sep 10, 2021 Last updated: Sep 10, 2021
Likely benign (Mar 06, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not Specified Affected status: unknown Allele origin: germline	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital Accession: SCV000864348.1 First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019	Comment: BS1, BP4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple … (more) BS1, BP4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). (less)
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Charcot-Marie-Tooth disease axonal type 2N Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135087.1 First in ClinVar: Jan 11, 2020 Last updated: Jan 11, 2020
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Charcot-Marie-Tooth disease axonal type 2N Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000398666.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Charcot-Marie-Tooth disease type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000259728.11 First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024
Benign (Oct 06, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001157286.4 First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024
Likely benign (-)	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: SCV005219089.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV000575058.32 First in ClinVar: Sep 04, 2014 Last updated: Oct 20, 2024	Comment: AARS1: BS1, BS2 Number of individuals with the variant: 60
non-pathogenic (-)	no assertion criteria provided Method: not provided	not provided Affected status: not provided Allele origin: unknown	Northcott Neuroscience Laboratory, ANZAC Research Institute Accession: SCV000188696.1 First in ClinVar: Sep 04, 2014 Last updated: Sep 04, 2014 Comment: CMT + Pyramidal signs	Comment: Converted during submission to Benign.
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001797941.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001922543.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001971775.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
not provided (-)	no classification provided Method: phenotyping only	Charcot-Marie-Tooth disease axonal type 2N Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000607057.1 First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017	Comment: GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more) GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Failure to thrive (present) , Short stature (present) , Abnormality of movement (present) , Generalized hypotonia (present) , Abnormality of coordination (present) , Cognitive impairment … (more) Failure to thrive (present) , Short stature (present) , Abnormality of movement (present) , Generalized hypotonia (present) , Abnormality of coordination (present) , Cognitive impairment (present) , Stereotypy (present) , Abnormality of the musculature of the limbs (present) , Abnormality of muscle physiology (present) , Abnormality of the large intestine (present) , Feeding difficulties (present) , Recurrent infections (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: female Testing laboratory: Baylor Genetics Date variant was reported to submitter: 2012-06-27 Testing laboratory interpretation: Uncertain significance
click to load more click to collapse

Comment:

BS1, BP4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

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 rs148355156 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001605.3(AARS1):c.1685C>T (p.Thr562Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs148355156 ...