NM_152268.4(PARS2):c.283G>A (p.Val95Ile) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Sep 7, 2022
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:: RCV000497433.8

Allele description [Variation Report for NM_152268.4(PARS2):c.283G>A (p.Val95Ile)]

NM_152268.4(PARS2):c.283G>A (p.Val95Ile)

Gene:

PARS2:prolyl-tRNA synthetase 2, mitochondrial [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p32.3

Genomic location:

Preferred name:

NM_152268.4(PARS2):c.283G>A (p.Val95Ile)

Other names:

PARS2, VAL95ILE (rs147227819)

HGVS:

NC_000001.11:g.54758879C>T
NG_042048.1:g.10675G>A
NM_152268.4:c.283G>AMANE SELECT
NP_689481.2:p.Val95Ile
NC_000001.10:g.55224552C>T
NM_152268.3:c.283G>A
NM_155268.3:c.283G>A

Protein change:

V95I; VAL95ILE

Links:

OMIM: 612036.0005; dbSNP: rs147227819

NCBI 1000 Genomes Browser:

rs147227819

Molecular consequence:

NM_152268.4:c.283G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000589806	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jul 21, 2022)	germline	clinical testing	Citation Link,
SCV003523297	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 7, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 28077841, 29915213, 30237576, 31130284, 32071833, 32514400, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000589806

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jul 21, 2022)

germline

clinical testing

Citation Link,

SCV003523297

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 7, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder.

Mizuguchi T, Nakashima M, Kato M, Yamada K, Okanishi T, Ekhilevitch N, Mandel H, Eran A, Toyono M, Sawaishi Y, Motoi H, Shiina M, Ogata K, Miyatake S, Miyake N, Saitsu H, Matsumoto N.

J Hum Genet. 2017 Apr;62(5):525-529. doi: 10.1038/jhg.2016.163. Epub 2017 Jan 12. Erratum in: J Hum Genet. 2017 Apr;62(5):587. doi: 10.1038/jhg.2017.13.

PubMed [citation]

PMID:: 28077841

The genotypic and phenotypic spectrum of PARS2-related infantile-onset encephalopathy.

Yin X, Tang B, Mao X, Peng J, Zeng S, Wang Y, Jiang H, Li N.

J Hum Genet. 2018 Sep;63(9):971-980. doi: 10.1038/s10038-018-0478-z. Epub 2018 Jun 18.

PubMed [citation]

PMID:: 29915213

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000589806.5

#	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 does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28077841, 29915213, 32071833, 30237576, 31130284, 31487502, 32514400, 34426522, 32533790, 32860008, 34484863, 34585293, Franz2020[paper], 34645488)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003523297.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This missense change has been observed in individuals with clinical features of PARS2-related conditions (PMID: 28077841, 29915213, 30237576, 31130284, 32071833, 32514400). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 432121). This variant is present in population databases (rs147227819, gnomAD 0.1%). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 95 of the PARS2 protein (p.Val95Ile).

#	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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