NM_003560.4(PLA2G6):c.2068G>A (p.Val690Ile) AND Infantile neuroaxonal dystrophy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 29, 2024
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:: RCV000821691.8

Allele description [Variation Report for NM_003560.4(PLA2G6):c.2068G>A (p.Val690Ile)]

NM_003560.4(PLA2G6):c.2068G>A (p.Val690Ile)

Gene:

PLA2G6:phospholipase A2 group VI [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q13.1

Genomic location:

Preferred name:

NM_003560.4(PLA2G6):c.2068G>A (p.Val690Ile)

HGVS:

NC_000022.11:g.38113621C>T
NG_007094.3:g.106158G>A
NG_033059.2:g.2049G>A
NM_001004426.3:c.1906G>A
NM_001199562.3:c.1906G>A
NM_001349864.2:c.2068G>A
NM_001349865.2:c.1906G>A
NM_001349866.2:c.1906G>A
NM_001349867.2:c.1534G>A
NM_001349868.2:c.1390G>A
NM_001349869.2:c.1372G>A
NM_003560.4:c.2068G>AMANE SELECT
NP_001004426.1:p.Val636Ile
NP_001186491.1:p.Val636Ile
NP_001336793.1:p.Val690Ile
NP_001336794.1:p.Val636Ile
NP_001336795.1:p.Val636Ile
NP_001336796.1:p.Val512Ile
NP_001336797.1:p.Val464Ile
NP_001336798.1:p.Val458Ile
NP_003551.2:p.Val690Ile
LRG_1015t1:c.2068G>A
LRG_1015:g.106158G>A
LRG_1015p1:p.Val690Ile
NC_000022.10:g.38509628C>T
NG_007094.2:g.97070G>A
NM_003560.2:c.2068G>A
NM_003560.3:c.2068G>A
p.Val690Ile

Protein change:

V458I

Links:

dbSNP: rs141777179

NCBI 1000 Genomes Browser:

rs141777179

Molecular consequence:

NM_001004426.3:c.1906G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001199562.3:c.1906G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349864.2:c.2068G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349865.2:c.1906G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349866.2:c.1906G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349867.2:c.1534G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349868.2:c.1390G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001349869.2:c.1372G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003560.4:c.2068G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Infantile neuroaxonal dystrophy (NBIA2A)
Synonyms:: NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 2A; Seitelberger disease; Infantile neuroaxonal dystrophy 1
Identifiers:: MONDO: MONDO:0024457; MedGen: C0270724; Orphanet: 35069; OMIM: 256600

Recent activity

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Putative beta-glucuronidase [Bacteroides caccae CL03T12C61]
Putative beta-glucuronidase [Bacteroides caccae CL03T12C61]
gi|2032994568|gnl|IGS|INE72_00773|g 06739.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000962460	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005086333	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 17, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 20886109, 27497490, 27848944, 29108286, 32870915, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000962460

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 29, 2024)

germline

clinical testing

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

SCV005086333

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 17, 2023)

germline

clinical testing

PubMed (6)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia-parkinsonism.

Engel LA, Jing Z, O'Brien DE, Sun M, Kotzbauer PT.

PLoS One. 2010 Sep 23;5(9):e12897. doi: 10.1371/journal.pone.0012897.

PubMed [citation]

PMID:: 20886109
PMCID:: PMC2944820

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000962460.4

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

Description

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 690 of the PLA2G6 protein (p.Val690Ile). This variant is present in population databases (rs141777179, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PLA2G6-related conditions. ClinVar contains an entry for this variant (Variation ID: 159754). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLA2G6 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005086333.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with infantile neuroaxonal dystrophy 1 (INAD; MIM#256600), neurodegeneration with brain iron accumulation 2B (NBIA; MIM#610217) and Parkinson disease 14 (MIM#612953). Variants with a loss of function effect result in INAD and NBIA, while missense variants resulting in increased enzyme activity cause Parkinson disease (PMID: 20886109, PMID: 29108286). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (135 heterozygotes, 0 homozygotes). (SP) 0504 - Same amino acid change has been observed in a placental mammal. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. However, the inframe deletion (p.Val691del) of one of two adjacent valine residues (p.Val690-p.Val691) has been reported many times as pathogenic, and was observed in several homozygous individuals with glial mitochondropathy or severe leukodystrophy with additional features (ClinVar, PMID: 27848944, PMID: 27497490). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been consistently reported as a VUS (LOVD, ClinVar), and was observed in a cohort of individuals with Parkinson disease (PMID: 32870915). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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: Oct 8, 2024

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