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NM_003560.4(PLA2G6):c.1894C>T (p.Arg632Trp) AND PLA2G6-associated neurodegeneration

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 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:
RCV002512836.3

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:
PLA2G6-associated neurodegeneration (PLAN)
Synonyms:
phospholipase A2-associated neurodegeneration
Identifiers:
MONDO: MONDO:0017998; MedGen: CN204472; Orphanet: 329303

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003760974Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely pathogenic
(Jan 24, 2023) 		germlinecuration

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003760974.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The p.Arg632Trp variant in PLA2G6 has been reported in 2 individuals with PLA2G6-associated neurodegeneration (PMID: 16783378, 19087156), segregated with disease in 2 affected relatives from 1 family (PMID: 19087156), and has been identified in 0.009% (2/21698) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121908683). 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#: 6199) and has been interpreted as pathogenic by OMIM, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), and CeGaT Praxis fuer Humangenetik Tuebingen. Of the 2 affected individuals, 1 of those was a homozygote, and 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Arg632Trp variant is pathogenic (Variant ID: 6198; PMID: 16783378, 19087156). The functional evidence for this variant is conflicting, and may not accurately depict the pathogenicity of the variant (PMID: 20886109, 29108286). 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: PM3, PP1_moderate, PP3, PM2_supporting (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 20, 2024