NM_020745.4(AARS2):c.647dup (p.Cys218fs) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 12, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000790768.17

Allele description [Variation Report for NM_020745.4(AARS2):c.647dup (p.Cys218fs)]

NM_020745.4(AARS2):c.647dup (p.Cys218fs)

Gene:

AARS2:alanyl-tRNA synthetase 2, mitochondrial [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

6p21.1

Genomic location:

Preferred name:

NM_020745.4(AARS2):c.647dup (p.Cys218fs)

HGVS:

NC_000006.12:g.44311097dup
NG_031952.1:g.7231dup
NM_020745.4:c.647dupMANE SELECT
NP_065796.2:p.Cys218fs
NC_000006.11:g.44278832_44278833insC
NC_000006.11:g.44278834dup
NM_020745.2:c.647dupG
NM_020745.3:c.647dupG

Protein change:

C218fs

Links:

OMIM: 612035.0003; dbSNP: rs587777589

NCBI 1000 Genomes Browser:

rs587777589

Molecular consequence:

NM_020745.4:c.647dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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LIM homeobox transcription factor 1-beta [Homo sapiens]
LIM homeobox transcription factor 1-beta [Homo sapiens]
gi|4505007|ref|NP_002307.1|

Protein
607989 (1)
OMIM

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000338713	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions)	Pathogenic (Feb 8, 2016)	germline	clinical testing	Citation Link,
SCV001591697	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 12, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25058219, 24808023, 30285085, 30819764, 28492532
SCV001793577	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 29, 2019)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000338713

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions)

Pathogenic
(Feb 8, 2016)

germline

clinical testing

Citation Link,

SCV001591697

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 12, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001793577

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Apr 29, 2019)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	3	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies.

Taylor RW, Pyle A, Griffin H, Blakely EL, Duff J, He L, Smertenko T, Alston CL, Neeve VC, Best A, Yarham JW, Kirschner J, Schara U, Talim B, Topaloglu H, Baric I, Holinski-Feder E, Abicht A, Czermin B, Kleinle S, Morris AA, Vassallo G, et al.

JAMA. 2014 Jul 2;312(1):68-77. doi: 10.1001/jama.2014.7184.

PubMed [citation]

PMID:: 25058219
PMCID:: PMC6558267

Novel (ovario) leukodystrophy related to AARS2 mutations.

Dallabona C, Diodato D, Kevelam SH, Haack TB, Wong LJ, Salomons GS, Baruffini E, Melchionda L, Mariotti C, Strom TM, Meitinger T, Prokisch H, Chapman K, Colley A, Rocha H, Ounap K, Schiffmann R, Salsano E, Savoiardo M, Hamilton EM, Abbink TE, Wolf NI, et al.

Neurology. 2014 Jun 10;82(23):2063-71. doi: 10.1212/WNL.0000000000000497. Epub 2014 May 7.

PubMed [citation]

PMID:: 24808023
PMCID:: PMC4118500

See all PubMed Citations (5)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000338713.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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		3	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001591697.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 143044). This variant is also known as c.647_648insG. This premature translational stop signal has been observed in individual(s) with multiple respiratory chain complex defects (PMID: 25058219). This variant is present in population databases (rs746514660, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Cys218Leufs*6) in the AARS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in AARS2 are known to be pathogenic (PMID: 24808023, 30285085, 30819764).

#	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

From GeneDx, SCV001793577.1

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

Description

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29971983, 30819764, 25058219)

#	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

Last Updated: Sep 29, 2024

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