ClinVar Genomic variation as it relates to human health
NM_003560.4(PLA2G6):c.2370T>G (p.Tyr790Ter)
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.
Pathogenic(19); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003560.4(PLA2G6):c.2370T>G (p.Tyr790Ter)
Variation ID: 6195 Accession: VCV000006195.63
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.1 22: 38112212 (GRCh38) [ NCBI UCSC ] 22: 38508219 (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 Aug 4, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003560.4:c.2370T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003551.2:p.Tyr790Ter nonsense NM_001004426.3:c.2208T>G NP_001004426.1:p.Tyr736Ter nonsense NM_001199562.3:c.2208T>G NP_001186491.1:p.Tyr736Ter nonsense NM_001349864.2:c.2370T>G NP_001336793.1:p.Tyr790Ter nonsense NM_001349865.2:c.2208T>G NP_001336794.1:p.Tyr736Ter nonsense NM_001349866.2:c.2208T>G NP_001336795.1:p.Tyr736Ter nonsense NM_001349867.2:c.1836T>G NP_001336796.1:p.Tyr612Ter nonsense NM_001349868.2:c.1692T>G NP_001336797.1:p.Tyr564Ter nonsense NM_001349869.2:c.1674T>G NP_001336798.1:p.Tyr558Ter nonsense NC_000022.11:g.38112212A>C NC_000022.10:g.38508219A>C NG_007094.3:g.107567T>G NG_033059.2:g.3458T>G LRG_1015:g.107567T>G LRG_1015t1:c.2370T>G LRG_1015p1:p.Tyr790Ter - Protein change
- Y790*, Y558*, Y564*, Y612*, Y736*
- Other names
- NM_003560.4(PLA2G6):c.2370T>G
- p.Tyr790Ter
- Canonical SPDI
- NC_000022.11:38112211:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- functionally_abnormal Sequence Ontology [SO:0002218]
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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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00006
Exome Aggregation Consortium (ExAC) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00010
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
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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 |
1059 | 1091 |
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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Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Jan 29, 2024 | RCV000006572.28 | |
Pathogenic (1) |
criteria provided, single submitter
|
Mar 17, 2014 | RCV000147321.7 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jul 1, 2022 | RCV000323935.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 20, 2016 | RCV000623021.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000763481.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2018 | RCV001333134.5 | |
Uncertain significance (1) |
criteria provided, single submitter
|
- | RCV001250474.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001813959.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 24, 2023 | RCV000778661.9 | |
PLA2G6-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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Sep 23, 2023 | RCV003407288.4 |
Pathogenic (1) |
criteria provided, single submitter
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May 24, 2022 | RCV002265549.2 | |
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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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Pathogenic
(Mar 17, 2014)
|
criteria provided, single submitter
Method: clinical testing
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iron accumulation in brain
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000194694.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Likely pathogenic
(Dec 03, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Infantile neuroaxonal dystrophy
Affected status: yes
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746537.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Age: 0-9 years
Sex: male
Geographic origin: Iran
|
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Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
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Infantile neuroaxonal dystrophy
Neurodegeneration with brain iron accumulation 2B Autosomal recessive Parkinson disease 14
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894264.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
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Pathogenic
(Oct 18, 2018)
|
criteria provided, single submitter
Method: clinical testing
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PLA2G6-associated neurodegeneration
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914994.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The PLA2G6 c.2370T>G (p.Tyr790Ter) variant is a stop-gained variant and has been reported in at least eight studies in a total of 11 probands with … (more)
The PLA2G6 c.2370T>G (p.Tyr790Ter) variant is a stop-gained variant and has been reported in at least eight studies in a total of 11 probands with PLA2G6-associated neurodegeneration, including in at least five in a homozygous state, in five in a compound heterozygous state, and in one in a heterozygous state (Morgan et al. 2006; Carrilho et al. 2008; Gregory et al. 2008; Pinto et al. 2010; Paisan-Ruiz 2012; Illingworth et al. 2014; Blake et al. 2016; Erro et al. 2016). Of note, another variant, c.2370_2371delTG, which also results in p.Tyr790Ter, has been reported in both a homozygous and compound heterozygous state in other probands. Control data are not available for the p.Tyr790Ter variant, which is reported at a frequency of 0.000148 in the Latino from the Genome Aggregation Database. In vitro studies examining the catalytic function of the p.Tyr790Ter variant demonstrated <10% phospholipase activity compared to wildtype in the presence of two different substrates (Engel et al. 2010). Based on the collective evidence, the p.Tyr790Ter variant is classified as pathogenic for PLA2G6-associated neurodegeneration. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Dec 27, 2018)
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criteria provided, single submitter
Method: clinical testing
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Infantile neuroaxonal dystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149880.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: female
Tissue: blood
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Infantile neuroaxonal dystrophy
Affected status: yes
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV001426444.1
First in ClinVar: Aug 06, 2020 Last updated: Aug 06, 2020 |
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Infantile neuroaxonal dystrophy
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002820331.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
The stop gained c.2370T>G (p.Y790*) in PLA2G6 (NM_003560.4) has been observed in the homozygous and compound heterozygous state in individuals affected with PLA2G6-related conditions (Morgan … (more)
The stop gained c.2370T>G (p.Y790*) in PLA2G6 (NM_003560.4) has been observed in the homozygous and compound heterozygous state in individuals affected with PLA2G6-related conditions (Morgan NV et al; Blake RB et al). Experimental studies have shown that this variant disrupts PLA2G6 enzymatic activity in vitro (Engel LA et al). The observed variant has been reported to ClinVar as Conflicting Interpretations Of Pathogenicity. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic (less)
Clinical Features:
Developmental regression (present) , Loss of speech (present) , Microcephaly (present) , Hypertonia (present) , Limb dystonia (present) , Delayed ability to roll over (present)
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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: SCV003761457.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Tyr790Ter variant in PLA2G6 has been reported in >10 individuals with PLA2G6-associated neurodegeneration (PMID: 33101984, 18359254, 18799783, 27378808, 30293248, 28716262, 16783378, 28600779, 30340910, 32860008, … (more)
The p.Tyr790Ter variant in PLA2G6 has been reported in >10 individuals with PLA2G6-associated neurodegeneration (PMID: 33101984, 18359254, 18799783, 27378808, 30293248, 28716262, 16783378, 28600779, 30340910, 32860008, 34602496, 35122944, Miryounesi 2018, 30868093, 34622992, 30537300, 33619735, 29859652, Silva 2014), segregated with disease in 2 affected relatives from 2 families (PMID: 28716262, 31196701), and has been identified in 0.02% (19/125174) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121908680). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 6195) and has been interpreted as pathogenic and likely pathogenic by multiple submitters, as well as a variant of uncertain significance by the Institute for Medical Genetics and Human Genetics (Charité - Universitätsmedizin Berlin). Of the 26 affected individuals, 12 of those were homozygotes, and 5 were compound heterozygotes that carried reported likely pathogenic variants in trans or with unknown phase, which increases the likelihood that the p.Tyr790Ter variant is pathogenic (Variant ID: 159741, 265448; PMID: 33101984, 18359254, 18799783, 27378808, 30293248, 28716262, 16783378, 28600779, 30340910, 32860008, 34602496, 35122944, Miryounesi 2018). In vitro functional studies provide some evidence that the p.Tyr790Ter variant impacts protein function (PMID: 20886109, 35122944). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 790. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the PLA2G6 gene is an established disease mechanism in autosomal recessive PLA2G6-associated neurodegeneration. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PVS1_moderate, PM3_very-strong, PP1, PS3_moderate (Richards 2015). (less)
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
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Neurodegeneration with brain iron accumulation 2B
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004101493.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The stop gained variant c.2370T>G (p.Tyr790Ter) in PLA2G6 gene has been reported in at least eight studies in a total of 11 probands with PLA2G6-associated … (more)
The stop gained variant c.2370T>G (p.Tyr790Ter) in PLA2G6 gene has been reported in at least eight studies in a total of 11 probands with PLA2G6-associated neurodegeneration (Morgan NV et.al.,2006). Functional studies demonstrate that this variant significantly impairs catalytic activity of the PLA2G6 protein (Engel et al., 2010). This variant has been reported to the ClinVar database as Pathogenic.The variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.009102% is reported in gnomAD. The nucleotide change in PLA2G6 is predicted as conserved by PhyloP across 100 vertebrates.For these reasons, this variant has been classified as Pathogenic (less)
Clinical Features:
Developmental regression (present) , Myoclonus (present)
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Pathogenic
(Sep 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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PLA2G6-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004113174.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The PLA2G6 c.2370T>G variant is predicted to result in premature protein termination (p.Tyr790*). This variant has been reported in the homozygous or compound heterozygous state … (more)
The PLA2G6 c.2370T>G variant is predicted to result in premature protein termination (p.Tyr790*). This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with infantile neuroaxonal dystrophy or neurodegeneration with brain iron accumulation (see for example, Gitiaux et al. 2018. PubMed ID: 29859652; AlBanji et al. 2020. PubMed ID: 33101984; Table S1, Brunet et al. 2021. PubMed ID: 33619735). An in vitro experimental study suggests this variant decreases enzymatic activity to less that 10% of wildtype activity (Figure 3, Engel et al. 2010. PubMed ID: 20886109). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-38508219-A-C). Nonsense variants in PLA2G6 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 22, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018846.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
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Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
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Infantile neuroaxonal dystrophy
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000832045.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr790*) in the PLA2G6 gene. While this is not anticipated to result in nonsense mediated decay, … (more)
This sequence change creates a premature translational stop signal (p.Tyr790*) in the PLA2G6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the PLA2G6 protein. This variant is present in population databases (rs121908680, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with clinical features of PLA2G6-related conditions (PMID: 16783378, 27378808; Invitae). ClinVar contains an entry for this variant (Variation ID: 6195). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PLA2G6 function (PMID: 20886109). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002585931.13
First in ClinVar: Oct 22, 2022 Last updated: Aug 04, 2024 |
Comment:
PLA2G6: PVS1, PM2
Number of individuals with the variant: 1
|
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Uncertain significance
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autism
Seizure (Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
|
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Accession: SCV001364070.1
First in ClinVar: Jul 30, 2020 Last updated: Jul 30, 2020 |
Comment:
We were able to detect the known pathogenic mutation c.2370T>G in the PLA2G6 gene in the patient in a heterozygous state. The variant was also … (more)
We were able to detect the known pathogenic mutation c.2370T>G in the PLA2G6 gene in the patient in a heterozygous state. The variant was also detected in the mother of the patient in heterozygous state. The PLA2G6 gene codes for phospholipase A2 of group 6 (MIM *603604). Biallelic pathogenic sequence variants in PLA2G6 have been described with three clinical manifestations of autosomal recessively inherited PLA2G6-associated neurodegeneration: 1) infantile neuroaxonal dystrophy (INAD, MIM: 256600), 2) neurodegeneration with iron accumulation in the brain (NBIA, MIM: 610217) and 3) PLA2G6-dependent dystonia parkinsonism (MIM: 612953). Clinical symptoms include psychomotor regression, symmetrical pyramidal trajectory signs, pronounced trunk hypotension, spastic quadriplegia, visual disturbances and dementia. The clinical course may be variable. The above variation leads to the formation of a premature stop codon and thus most likely to the premature termination of protein biosynthesis. The variant has already been reported in numerous patients in homozygous or compound-heterozygous condition (HGMD: CM063050). The sequence variant is listed in gnomAD 25x in heterozygous state and occurs in the European subpopulation with an allele frequency of 0.015%. (less)
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Pathogenic
(Jan 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodegeneration with brain iron accumulation 2B
Affected status: yes
Allele origin:
paternal
|
Baylor Genetics
Accession: SCV001525629.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 16783378, 27378808, 20886109]
|
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Pathogenic
(Jul 10, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Abnormality of the nervous system
Affected status: yes
Allele origin:
germline
|
Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755400.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
|
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Pathogenic
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Infantile neuroaxonal dystrophy
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002518870.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
|
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Pathogenic
(May 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodegeneration with brain iron accumulation
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002548273.1
First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022 |
Comment:
Variant summary: PLA2G6 c.2370T>G (p.Tyr790X) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein, … (more)
Variant summary: PLA2G6 c.2370T>G (p.Tyr790X) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.2e-05 in 243312 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PLA2G6 (8.2e-05 vs 0.00085), allowing no conclusion about variant significance. c.2370T>G has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with features of PLA2G6-associated neurodegeneration (PLAN), predominantly as infantile neuroaxonal dystrophy (INAD) (example, Carrilho_2008, Gregory_2008, Darling_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal Phospholipase and lysophospholipase catalytic activities in-vitro (example, Engel_2010). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Infantile neuroaxonal dystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Baylor Genetics
Accession: SCV000807614.2
First in ClinVar: May 30, 2018 Last updated: Dec 11, 2022 |
Comment:
This variant has been previously reported as disease-causing and was found twice in our laboratory with another variant in affected individuals: a 2-year-old male with … (more)
This variant has been previously reported as disease-causing and was found twice in our laboratory with another variant in affected individuals: a 2-year-old male with regression, hearing loss, hypotonia, failure to thrive, cerebellar atrophy, vision loss; a 5-year-old female with regression, dystonia, epilepsy, microcephaly, failure to thrive, cerebellar atrophy. Heterozygotes would be expected to be asymptomatic carriers. (less)
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Pathogenic
(Jun 20, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000741629.3
First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Developmental regression (present) , Muscular hypotonia of the trunk (present) , Vertical nystagmus (present) , Cerebellar atrophy (present) , Macrocephalus (present) , Growth delay (present) … (more)
Developmental regression (present) , Muscular hypotonia of the trunk (present) , Vertical nystagmus (present) , Cerebellar atrophy (present) , Macrocephalus (present) , Growth delay (present) , 2-3 toe syndactyly (present) , Muscle weakness (present) , Absent speech (present) , Inability to walk (present) (less)
Sex: female
Ethnicity/Population group: African American
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Pathogenic
(Mar 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329472.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Functional studies demonstrate that this variant significantly impairs catalytic activity of the PLA2G6 protein (Engel et al., 2010); Nonsense variant in the C-terminus predicted to … (more)
Functional studies demonstrate that this variant significantly impairs catalytic activity of the PLA2G6 protein (Engel et al., 2010); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 17 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 18359254, 20886109, 16783378, 27378808, 28600779, 24800972, 18443314, 24847269, 18570303, 24745848, 30537300, 30340910, 20619503, 33101984, 31589614) (less)
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Pathogenic
(Jul 01, 2006)
|
no assertion criteria provided
Method: literature only
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NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 2A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000026755.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 05, 2015 |
Comment on evidence:
In a proband with classic infantile neuroaxonal dystrophy (NBIA2A; 256600), Morgan et al. (2006) identified a 2370T-G transversion in exon 17 of the PLA2G6 gene … (more)
In a proband with classic infantile neuroaxonal dystrophy (NBIA2A; 256600), Morgan et al. (2006) identified a 2370T-G transversion in exon 17 of the PLA2G6 gene that was predicted to result in a premature termination in the protein (tyr790 to stop; Y790X). The parents were known to be consanguineous and the mutation was present in homozygous state. The presence of spheroids had been demonstrated. (less)
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Pathogenic
(Dec 30, 2017)
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no assertion criteria provided
Method: curation
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Infantile neuroaxonal dystrophy
Affected status: yes
Allele origin:
unknown
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Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University
Accession: SCV000891660.1
First in ClinVar: Mar 22, 2019 Last updated: Mar 22, 2019 |
Geographic origin: Middle East
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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functionally_abnormal
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Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin
Accession: SCV001364070.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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PLA2G6-associated neurodegeneration: New insights into brain abnormalities and disease progression. | Darling A | Parkinsonism & related disorders | 2019 | PMID: 30340910 |
New genetic causes for complex hereditary spastic paraplegia. | Souza PVS | Journal of the neurological sciences | 2017 | PMID: 28716262 |
Child Neurology: Two sisters with dystonia and regression: PLA2G6-associated neurodegeneration. | Blake RB | Neurology | 2016 | PMID: 27378808 |
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 |
Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia-parkinsonism. | Engel LA | PloS one | 2010 | PMID: 20886109 |
Neurodegeneration associated with genetic defects in phospholipase A(2). | Gregory A | Neurology | 2008 | PMID: 18799783 |
Infantile neuroaxonal dystrophy: what's most important for the diagnosis? | Carrilho I | European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society | 2008 | PMID: 18359254 |
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 rs121908680 ...
HelpRecord last updated Aug 04, 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.