U.S. flag

An official website of the United States government

NM_020442.6(VARS2):c.1168G>A (p.Ala390Thr) AND Combined oxidative phosphorylation defect type 20

Germline classification:
Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:
Dec 18, 2023
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:
RCV000625984.10

Allele description [Variation Report for NM_020442.6(VARS2):c.1168G>A (p.Ala390Thr)]

NM_020442.6(VARS2):c.1168G>A (p.Ala390Thr)

Gene:
VARS2:valyl-tRNA synthetase 2, mitochondrial [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
6p21.33
Genomic location:
Preferred name:
NM_020442.6(VARS2):c.1168G>A (p.Ala390Thr)
HGVS:
  • NC_000006.12:g.30920091G>A
  • NG_034224.1:g.10884G>A
  • NM_001167733.3:c.748G>A
  • NM_001167734.2:c.1258G>A
  • NM_020442.6:c.1168G>AMANE SELECT
  • NP_001161205.1:p.Ala250Thr
  • NP_001161206.1:p.Ala420Thr
  • NP_001161206.1:p.Ala420Thr
  • NP_065175.4:p.Ala390Thr
  • NC_000006.11:g.30887868G>A
  • NM_001167734.1:c.1258G>A
  • p.A420T
Protein change:
A250T; ALA420THR
Links:
OMIM: 612802.0005; dbSNP: rs202201763
NCBI 1000 Genomes Browser:
rs202201763
Molecular consequence:
  • NM_001167733.3:c.748G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167734.2:c.1258G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_020442.6:c.1168G>A - missense variant - [Sequence Ontology: SO:0001583]
Functional consequence:
Decreased function
Observations:
1

Condition(s)

Name:
Combined oxidative phosphorylation defect type 20
Synonyms:
Combined oxidative phosphorylation deficiency 20
Identifiers:
MONDO: MONDO:0014397; MedGen: C4014660; Orphanet: 420728; OMIM: 615917

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000746589Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(May 4, 2017)
paternalclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001137065Mendelics
criteria provided, single submitter

(Mendelics Assertion Criteria 2017)
Pathogenic
(May 28, 2019)
unknownclinical testing

Citation Link,

SCV001372473OMIM
no assertion criteria provided
Pathogenic
(Jul 10, 2020)
germlineliterature only

PubMed (1)
[See all records that cite this PMID]

SCV001481167Department of Pediatrics, Salzburger Landeskliniken & Paracelsus Medical University
no assertion criteria provided
Pathogenic
(Feb 22, 2021)
not applicableclinical testing

SCV004241293Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Dec 18, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providednot applicablenot applicablenot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
Hispanicpaternalyes1not providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Clinical, biochemical, and genetic features associated with VARS2-related mitochondrial disease.

Bruni F, Di Meo I, Bellacchio E, Webb BD, McFarland R, Chrzanowska-Lightowlers ZMA, He L, Skorupa E, Moroni I, Ardissone A, Walczak A, Tyynismaa H, Isohanni P, Mandel H, Prokisch H, Haack T, Bonnen PE, Enrico B, Pronicka E, Ghezzi D, Taylor RW, Diodato D.

Hum Mutat. 2018 Apr;39(4):563-578. doi: 10.1002/humu.23398. Epub 2018 Feb 7.

PubMed [citation]
PMID:
29314548
PMCID:
PMC5873438
See all PubMed Citations (4)

Details of each submission

From Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN, SCV000746589.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1Hispanic1not providednot providedclinical testing
(GTR000553916.1)
PubMed (1)

Description

This variant was found in trans with another variant (c.1076-14A>G) in a 6-year-old male with severe neurodevelopmental impairment, encephalopathy, microcephaly, hypertrophic cardiomyopathy, lactic acidosis, seizure disorder (infantile spasms), abnormal MRI showing brain and brainstem atrophy.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1paternalyesnot providednot providednot provided
(GTR000553916.1)
1not providednot providednot provided

From Mendelics, SCV001137065.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From OMIM, SCV001372473.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (1)

Description

In 3 patients (P8, P9, P10) from 2 unrelated Mexican families (families 7 and 8) with combined oxidative phosphorylation deficiency-20 (COXPD20; 615917), Bruni et al. (2018) identified homozygosity for a c.1258G-A transition (c.1258G-A, NM_001167734.1) in the VARS2 gene, resulting in an ala420-to-thr (A420T) substitution in a region important for the interaction of VARS2 with the cognate mRNA. The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. The parents were heterozygous for the mutation. The A420T variant had a frequency of 0.0312% in the ExAC database. Functional studies were not performed. The patients had infantile-onset hypertrophic cardiomyopathy, elevated plasma lactate, and hypotonia.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Department of Pediatrics, Salzburger Landeskliniken & Paracelsus Medical University, SCV001481167.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not applicablenot applicablenot providedmusclenot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004241293.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: VARS2 c.1168G>A (p.Ala390Thr) results in a non-conservative amino acid change located in the Aminoacyl-tRNA synthetase, class Ia domain (IPR002300) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 1534628 control chromosomes (gnomAD V4.0). The variant, c.1168G>A (aka. c.1258G>A, p.Ala420Thr), has been reported in the literature in multiple individuals affected with Combined Oxidative Phosphorylation Defect Type 20 (Bruni_2018, Kusikova_2021). One of these publications reported that VARS2 protein was deficient in patient derived muscle biopsy, and the resulting defect of oxidative phosphorylation was also demonstrated by enzymatic assay (Kusikova_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 29314548, 33937156, 34216551). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 3, 2024