ClinVar Genomic variation as it relates to human health
NM_003560.4(PLA2G6):c.1798C>T (p.Arg600Trp)
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.1798C>T (p.Arg600Trp)
Variation ID: 1197568 Accession: VCV001197568.6
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.1 22: 38116156 (GRCh38) [ NCBI UCSC ] 22: 38512163 (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 Aug 14, 2021 Feb 14, 2024 Feb 22, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003560.4:c.1798C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003551.2:p.Arg600Trp missense NM_001004426.3:c.1636C>T NP_001004426.1:p.Arg546Trp missense NM_001199562.3:c.1636C>T NP_001186491.1:p.Arg546Trp missense NM_001349864.2:c.1798C>T NP_001336793.1:p.Arg600Trp missense NM_001349865.2:c.1636C>T NP_001336794.1:p.Arg546Trp missense NM_001349866.2:c.1636C>T NP_001336795.1:p.Arg546Trp missense NM_001349867.2:c.1264C>T NP_001336796.1:p.Arg422Trp missense NM_001349868.2:c.1120C>T NP_001336797.1:p.Arg374Trp missense NM_001349869.2:c.1102C>T NP_001336798.1:p.Arg368Trp missense NC_000022.11:g.38116156G>A NC_000022.10:g.38512163G>A NG_007094.3:g.103623C>T LRG_1015:g.103623C>T LRG_1015t1:c.1798C>T LRG_1015p1:p.Arg600Trp - Protein change
- R368W, R374W, R422W, R546W, R600W
- Other names
- NM_003560.4(PLA2G6):c.1798C>T
- p.Arg600Trp
- Canonical SPDI
- NC_000022.11:38116155:G:A
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00003
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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 |
1054 | 1086 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Apr 16, 2021 | RCV001561435.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 5, 2022 | RCV002266002.1 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002569014.2 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 22, 2023 | RCV003507377.1 |
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
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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
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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
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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
(Apr 16, 2021)
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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: SCV001784043.1
First in ClinVar: Aug 14, 2021 Last updated: Aug 14, 2021 |
Comment:
Observed with a second disease associated variant, phase (cis or trans) unknown, in a patient with neuroaxonal dystrophy in published literature (Illingworth et al., 2014).; … (more)
Observed with a second disease associated variant, phase (cis or trans) unknown, in a patient with neuroaxonal dystrophy in published literature (Illingworth et al., 2014).; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also denoted as R546W due to alternative nomenclature; This variant is associated with the following publications: (PMID: 24745848, 31516627, 32357911) (less)
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Pathogenic
(May 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002548272.1
First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
Comment:
Variant summary: PLA2G6 c.1798C>T (p.Arg600Trp) results in a non-conservative amino acid change located in the Patatin-like phospholipase domain (IPR002641) of the encoded protein sequence. Five … (more)
Variant summary: PLA2G6 c.1798C>T (p.Arg600Trp) results in a non-conservative amino acid change located in the Patatin-like phospholipase domain (IPR002641) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251070 control chromosomes (gnomAD). c.1798C>T has been reported in the literature in multiple compound heterozygous individuals affected with PLA2G6-associated neurodegeneration (Illingworth_2014, Jain_2019, Altuame_2020). Additionally, this variant was found in three affected siblings and co-segregated with disease (Toth-Bencsik_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Another missense variant (p.Arg600Gln) at the same residue was found in patients with Infantile neuroaxonal dystrophy (Kapoor_2016, HGMD database) and has been classified as likely pathogenic/pathogenic in ClinVar, suggesting that it is a clinically significant residue. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was 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: SCV003760976.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Arg600Trp variant in PLA2G6 has been reported in 4 individuals with PLA2G6-associated neurodegeneration (PMID: 24745848, 34168672, 31516627, 32357911), and has been identified in 0.005% … (more)
The p.Arg600Trp variant in PLA2G6 has been reported in 4 individuals with PLA2G6-associated neurodegeneration (PMID: 24745848, 34168672, 31516627, 32357911), and has been identified in 0.005% (1/18392) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs368008077). 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#: 159741) and has been interpreted as likely pathogenic by GeneDx. Of the 4 affected individuals, 2 were compound heterozygotes that carried reported likely pathogenic variants in trans and with unknown phase, 1 was a compound heterozygote that carried a variant of uncertain significance in trans, and 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Arg600Trp variant is pathogenic (Variant ID: 159749, 265448; PMID: 24745848, 34168672, 31516627, 32357911). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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: PP3, PM2_supporting, PM3_strong (Richards 2015). (less)
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Pathogenic
(Feb 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: SCV004300023.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 600 of the PLA2G6 protein … (more)
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 600 of the PLA2G6 protein (p.Arg600Trp). This variant is present in population databases (rs368008077, gnomAD 0.006%). This missense change has been observed in individual(s) with infantile neuroaxonal dystrophy (PMID: 24745848, 31516627, 34168672). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.R546W. ClinVar contains an entry for this variant (Variation ID: 1197568). 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.Arg600 amino acid residue in PLA2G6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20619503, 26668131, 33619735). 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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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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New Insights of Phospholipase A2 Associated Neurodegeneration Phenotype Based on the Long-Term Follow-Up of a Large Hungarian Family. | Toth-Bencsik R | Frontiers in genetics | 2021 | PMID: 34168672 |
De novo variants in neurodevelopmental disorders-experiences from a tertiary care center. | Brunet T | Clinical genetics | 2021 | PMID: 33619735 |
The natural history of infantile neuroaxonal dystrophy. | Altuame FD | Orphanet journal of rare diseases | 2020 | PMID: 32357911 |
Atypical Childhood-onset Neuroaxonal Dystrophy in an Indian Girl. | Jain S | Journal of pediatric neurosciences | 2019 | PMID: 31516627 |
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 |
Disruption of Golgi morphology and altered protein glycosylation in PLA2G6-associated neurodegeneration. | Davids M | Journal of medical genetics | 2016 | PMID: 26668131 |
Novel PLA2G6 mutations associated with an exonic deletion due to non-allelic homologous recombination in a patient with infantile neuroaxonal dystrophy. | Yamamoto T | Human genome variation | 2015 | PMID: 27081553 |
PLA2G6-associated neurodegeneration (PLAN): further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease. | Illingworth MA | Molecular genetics and metabolism | 2014 | PMID: 24745848 |
Widespread Lewy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. | Paisán-Ruiz C | Neurobiology of aging | 2012 | PMID: 20619503 |
Text-mined citations for rs368008077 ...
HelpRecord last updated May 27, 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.