NM_003560.4(PLA2G6):c.1894C>T (p.Arg632Trp) AND Infantile neuroaxonal dystrophy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 22, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003507245.2

Allele description [Variation Report for NM_003560.4(PLA2G6):c.1894C>T (p.Arg632Trp)]

NM_003560.4(PLA2G6):c.1894C>T (p.Arg632Trp)

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.1894C>T (p.Arg632Trp)

Other names:

NM_003560.4(PLA2G6):c.1894C>T

HGVS:

NC_000022.11:g.38115667G>A
NG_007094.3:g.104112C>T
NG_033059.2:g.3C>T
NM_001004426.3:c.1732C>T
NM_001199562.3:c.1732C>T
NM_001349864.2:c.1894C>T
NM_001349865.2:c.1732C>T
NM_001349866.2:c.1732C>T
NM_001349867.2:c.1360C>T
NM_001349868.2:c.1216C>T
NM_001349869.2:c.1198C>T
NM_003560.4:c.1894C>TMANE SELECT
NP_001004426.1:p.Arg578Trp
NP_001186491.1:p.Arg578Trp
NP_001336793.1:p.Arg632Trp
NP_001336794.1:p.Arg578Trp
NP_001336795.1:p.Arg578Trp
NP_001336796.1:p.Arg454Trp
NP_001336797.1:p.Arg406Trp
NP_001336798.1:p.Arg400Trp
NP_003551.2:p.Arg632Trp
LRG_1015t1:c.1894C>T
LRG_1015:g.104112C>T
LRG_1015p1:p.Arg632Trp
NC_000022.10:g.38511674G>A
NC_000022.10:g.38511674G>A
NG_007094.2:g.95024C>T
NM_003560.2:c.1894C>T
O60733:p.Arg632Trp

Protein change:

R400W; ARG632TRP

Links:

UniProtKB: O60733#VAR_029373; OMIM: 603604.0005; dbSNP: rs121908683

NCBI 1000 Genomes Browser:

rs121908683

Molecular consequence:

NM_001004426.3:c.1732C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001199562.3:c.1732C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349864.2:c.1894C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349865.2:c.1732C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349866.2:c.1732C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349867.2:c.1360C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349868.2:c.1216C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001349869.2:c.1198C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003560.4:c.1894C>T - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004300022	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 22, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16783378, 19087156, 20886109, 29108286, 34520727, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004300022

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 22, 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

PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron.

Morgan NV, Westaway SK, Morton JE, Gregory A, Gissen P, Sonek S, Cangul H, Coryell J, Canham N, Nardocci N, Zorzi G, Pasha S, Rodriguez D, Desguerre I, Mubaidin A, Bertini E, Trembath RC, Simonati A, Schanen C, Johnson CA, Levinson B, Woods CG, et al.

Nat Genet. 2006 Jul;38(7):752-4. Epub 2006 Jun 18. Erratum in: Nat Genet. 2006 Aug;38(8):957.

PubMed [citation]

PMID:: 16783378
PMCID:: PMC2117328

R632W mutation in PLA2G6 segregates with dystonia-parkinsonism in a consanguineous Iranian family.

Sina F, Shojaee S, Elahi E, Paisán-Ruiz C.

Eur J Neurol. 2009 Jan;16(1):101-4. doi: 10.1111/j.1468-1331.2008.02356.x.

PubMed [citation]

PMID:: 19087156

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004300022.1

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

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 632 of the PLA2G6 protein (p.Arg632Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with PLA2G6 associated conditions (PMID: 16783378, 19087156). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6199). 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 expected to disrupt PLA2G6 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PLA2G6 function (PMID: 20886109, 29108286, 34520727). 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

Last Updated: Oct 20, 2024

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