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:

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000746589	Undiagnosed Diseases Network, NIH - Undiagnosed Diseases Network (NIH), UDN	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 4, 2017)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001137065	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001372473	OMIM	no assertion criteria provided	Pathogenic (Jul 10, 2020)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001481167	Department of Pediatrics, Salzburger Landeskliniken & Paracelsus Medical University	no assertion criteria provided	Pathogenic (Feb 22, 2021)	not applicable	clinical testing
SCV004241293	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29314548, 33937156, 34216551 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Hispanic	paternal	yes	1	not provided	not provided	not provided	not provided	clinical 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

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	yes	not provided	not provided	not provided	(GTR000553916.1)	1	not provided	not provided	not provided

From Mendelics, SCV001137065.1

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

From OMIM, SCV001372473.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

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

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

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

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

#	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

Last Updated: Sep 29, 2024

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