NM_020442.6(VARS2):c.1168G>A (p.Ala390Thr) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jan 22, 2024
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:: RCV000676486.27

Allele description

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000802269	Mayo Clinic Laboratories, Mayo Clinic	no assertion criteria provided	Uncertain significance (Oct 25, 2017)	unknown	clinical testing
SCV001987432	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Nov 6, 2023)	germline	clinical testing	Citation Link,
SCV002304175	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29314548, 33937156, 28492532
SCV002586104	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Aug 1, 2022)	germline	clinical testing	Citation Link

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Summary from all submissions

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

Citations

PubMed

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

Case Report and Review of the Literature: A New and a Recurrent Variant in the VARS2 Gene Are Associated With Isolated Lethal Hypertrophic Cardiomyopathy, Hyperlactatemia, and Pulmonary Hypertension in Early Infancy.

Kušíková K, Feichtinger RG, Csillag B, Kalev OK, Weis S, Duba HC, Mayr JA, Weis D.

Front Pediatr. 2021;9:660076. doi: 10.3389/fped.2021.660076.

PubMed [citation]

PMID:: 33937156
PMCID:: PMC8085550

See all PubMed Citations (3)

Details of each submission

From Mayo Clinic Laboratories, Mayo Clinic, SCV000802269.1

#	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 GeneDx, SCV001987432.5

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33937156, 34484863, 31623496, 29314548, 30458719, 34216551)

#	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

From Invitae, SCV002304175.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 420 of the VARS2 protein (p.Ala420Thr). This variant is present in population databases (rs202201763, gnomAD 0.2%). This missense change has been observed in individual(s) with clinical features of VARS2-related conditions (PMID: 29314548, 33937156; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 522814). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as 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

From CeGaT Center for Human Genetics Tuebingen, SCV002586104.11

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

Description

VARS2: PM3, PM2:Supporting

#	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		1	not provided	not provided	not provided

Last Updated: Jul 7, 2024

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