NM_003560.4(PLA2G6):c.2215G>C (p.Asp739His) AND Infantile neuroaxonal dystrophy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 24, 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:: RCV000793778.8

Allele description [Variation Report for NM_003560.4(PLA2G6):c.2215G>C (p.Asp739His)]

NM_003560.4(PLA2G6):c.2215G>C (p.Asp739His)

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.2215G>C (p.Asp739His)

Other names:

NM_003560.4(PLA2G6):c.2215G>C; p.Asp739His

HGVS:

NC_000022.11:g.38112565C>G
NG_007094.3:g.107214G>C
NG_033059.2:g.3105G>C
NM_001004426.3:c.2053G>C
NM_001199562.3:c.2053G>C
NM_001349864.2:c.2215G>C
NM_001349865.2:c.2053G>C
NM_001349866.2:c.2053G>C
NM_001349867.2:c.1681G>C
NM_001349868.2:c.1537G>C
NM_001349869.2:c.1519G>C
NM_003560.4:c.2215G>CMANE SELECT
NP_001004426.1:p.Asp685His
NP_001186491.1:p.Asp685His
NP_001336793.1:p.Asp739His
NP_001336794.1:p.Asp685His
NP_001336795.1:p.Asp685His
NP_001336796.1:p.Asp561His
NP_001336797.1:p.Asp513His
NP_001336798.1:p.Asp507His
NP_003551.2:p.Asp739His
LRG_1015t1:c.2215G>C
LRG_1015:g.107214G>C
LRG_1015p1:p.Asp739His
NC_000022.10:g.38508572C>G
NG_007094.2:g.98126G>C
NM_003560.2:c.2215G>C

Protein change:

D507H

Links:

dbSNP: rs587784349

NCBI 1000 Genomes Browser:

rs587784349

Molecular consequence:

NM_001004426.3:c.2053G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001199562.3:c.2053G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001349864.2:c.2215G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001349865.2:c.2053G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001349866.2:c.2053G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001349867.2:c.1681G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001349868.2:c.1537G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001349869.2:c.1519G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_003560.4:c.2215G>C - 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
SCV000933150	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16783378, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000933150

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 24, 2023)

germline

clinical testing

PubMed (2)
[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

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000933150.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 739 of the PLA2G6 protein (p.Asp739His). This variant is present in population databases (rs587784349, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of PLA2G6-related conditions (PMID: 16783378; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 159761). 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%. 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: Sep 29, 2024

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