ClinVar Genomic variation as it relates to human health
NM_003560.4(PLA2G6):c.1613G>A (p.Arg538His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003560.4(PLA2G6):c.1613G>A (p.Arg538His)
Variation ID: 159739 Accession: VCV000159739.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.1 22: 38120888 (GRCh38) [ NCBI UCSC ] 22: 38516895 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Nov 23, 2014 Feb 14, 2024 Oct 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003560.4:c.1613G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003551.2:p.Arg538His missense NM_001004426.3:c.1451G>A NP_001004426.1:p.Arg484His missense NM_001199562.3:c.1451G>A NP_001186491.1:p.Arg484His missense NM_001349864.2:c.1613G>A NP_001336793.1:p.Arg538His missense NM_001349865.2:c.1451G>A NP_001336794.1:p.Arg484His missense NM_001349866.2:c.1451G>A NP_001336795.1:p.Arg484His missense NM_001349867.2:c.1079G>A NP_001336796.1:p.Arg360His missense NM_001349868.2:c.935G>A NP_001336797.1:p.Arg312His missense NM_001349869.2:c.917G>A NP_001336798.1:p.Arg306His missense NC_000022.11:g.38120888C>T NC_000022.10:g.38516895C>T NG_007094.3:g.98891G>A LRG_1015:g.98891G>A LRG_1015t1:c.1613G>A LRG_1015p1:p.Arg538His - Protein change
- R538H, R306H, R312H, R484H, R360H
- Other names
- NM_003560.4(PLA2G6):c.1613G>A
- p.Arg538His
- Canonical SPDI
- NC_000022.11:38120887:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PLA2G6 | - | - |
GRCh38 GRCh37 |
1041 | 1072 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Likely pathogenic (1) |
criteria provided, single submitter
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Feb 8, 2013 | RCV000147294.6 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 23, 2022 | RCV000412963.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 22, 2023 | RCV001849993.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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- | RCV001823117.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002514833.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Feb 08, 2013)
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criteria provided, single submitter
Method: clinical testing
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iron accumulation in brain
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000194667.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation 2B
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073030.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The missense variant p.R538H in PLA2G6 (NM_003560.4) has been reported previously in individuals with infantile neuroaxonal dystrophy (INAD) (Megahed et al, 2016; Kapoor et al, … (more)
The missense variant p.R538H in PLA2G6 (NM_003560.4) has been reported previously in individuals with infantile neuroaxonal dystrophy (INAD) (Megahed et al, 2016; Kapoor et al, 2016). It has been submitted to the ClinVar database as Pathogenic. Another missense affecting the same amino acid has also been reported to be disease causing (Morgan T et al, 2006). The p.R538H variant is observed in 2/30,616 (0.0065%) alleles from individuals of South Asian background in gnomAD Exomes and in 1/978 (0.1022%) alleles from individuals of South Asian background in 1000 Genomes. The p.R538H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 538 of PLA2G6 is conserved in all mammalian species. The nucleotide c.1613 in PLA2G6 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. (less)
Clinical Features:
Atypical behavior (present) , Gait disturbance (present) , Slurred speech (present) , Inability to walk (present) , Cerebral atrophy (present) , Cerebellar atrophy (present)
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Likely pathogenic
(Aug 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000490725.5
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27146152, 27196560, 33144682, 32771225) (less)
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Pathogenic
(Oct 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Infantile neuroaxonal dystrophy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002304092.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 538 of the PLA2G6 protein (p.Arg538His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 538 of the PLA2G6 protein (p.Arg538His). This variant is present in population databases (rs535486098, gnomAD 0.006%). This missense change has been observed in individuals with infantile neuroaxonal dystrophy and/or Parkinson disease (PMID: 27146152, 27196560, 32771225). ClinVar contains an entry for this variant (Variation ID: 159739). 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. This variant disrupts the p.Arg538Cys amino acid residue in PLA2G6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16783378, 24252552, 32771225; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Jan 24, 2023)
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criteria provided, single submitter
Method: curation
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PLA2G6-associated neurodegeneration
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003760986.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Arg538His variant in PLA2G6 has been reported in 5 individuals with PLA2G6-associated neurodegeneration (PMID: 27196560, 27146152, 33144682, Agarwal_2020, 32771225), segregated with disease in 2 … (more)
The p.Arg538His variant in PLA2G6 has been reported in 5 individuals with PLA2G6-associated neurodegeneration (PMID: 27196560, 27146152, 33144682, Agarwal_2020, 32771225), segregated with disease in 2 affected relatives from 2 families (Agarwal_2020) and has been identified in 0.007% (2/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs535486098). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 159739) and has been interpreted as pathogenic or likely pathogenic by Genetic Services Laboratory (University of Chicago), Neuberg Supratech Reference Laboratories Pvt Ltd (Neuberg Centre for Genomic Medicine), GeneDx, and Invitae. Of the 5 affected individuals, 4 of those were homozygotes, which increases the likelihood that the p.Arg538His variant is pathogenic (PMID: 27196560, 27146152, 33144682, Agarwal_2020). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of an individual homozygous for this variant is highly specific for PLA2G6-associated neurodegeneration based on brain iron accumulation on MRI consistent with disease (PMID: 27196560). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PM2, PM3, PP1, PP4 (Richards 2015). (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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PLA2G6 variants associated with the number of affected alleles in Parkinson's disease in Japan. | Daida K | Neurobiology of aging | 2021 | PMID: 32771225 |
Genetic Analysis of PLA2G6 in 22 Indian Families with Infantile Neuroaxonal Dystrophy, Atypical Late-Onset Neuroaxonal Dystrophy and Dystonia Parkinsonism Complex. | Kapoor S | PloS one | 2016 | PMID: 27196560 |
Utility of whole exome sequencing for the early diagnosis of pediatric-onset cerebellar atrophy associated with developmental delay in an inbred population. | Megahed H | Orphanet journal of rare diseases | 2016 | PMID: 27146152 |
Extensive aggregation of α-synuclein and tau in juvenile-onset neuroaxonal dystrophy: an autopsied individual with a novel mutation in the PLA2G6 gene-splicing site. | Riku Y | Acta neuropathologica communications | 2013 | PMID: 24252552 |
PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. | Morgan NV | Nature genetics | 2006 | PMID: 16783378 |
Text-mined citations for rs535486098 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.