VCV002581741.3 - ClinVar

NM_003560.4(PLA2G6):c.967G>A (p.Val323Met)

Germline

Classification

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.

(3)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003560.4(PLA2G6):c.967G>A (p.Val323Met)

Variation ID: 2581741 Accession: VCV002581741.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q13.1 22: 38132941 (GRCh38) [ NCBI UCSC ] 22: 38528948 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Oct 7, 2023	Feb 28, 2024	Dec 31, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003560.4:c.967G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003551.2:p.Val323Met	missense
NM_001004426.3:c.967G>A	NP_001004426.1:p.Val323Met	missense
NM_001199562.3:c.967G>A	NP_001186491.1:p.Val323Met	missense
NM_001349864.2:c.967G>A	NP_001336793.1:p.Val323Met	missense
NM_001349865.2:c.967G>A	NP_001336794.1:p.Val323Met	missense
NM_001349866.2:c.967G>A	NP_001336795.1:p.Val323Met	missense
NM_001349867.2:c.433G>A	NP_001336796.1:p.Val145Met	missense
NM_001349868.2:c.289G>A	NP_001336797.1:p.Val97Met	missense
NM_001349869.2:c.433G>A	NP_001336798.1:p.Val145Met	missense
NC_000022.11:g.38132941C>T
NC_000022.10:g.38528948C>T
NG_007094.3:g.86838G>A
LRG_1015:g.86838G>A
LRG_1015t1:c.967G>A	LRG_1015p1:p.Val323Met

... more HGVS ... less HGVS

Protein change

V145M, V323M, V97M

Other names

Canonical SPDI

NC_000022.11:38132940:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

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
Gene	OMIM	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.
PLA2G6		-	-	GRCh38 GRCh37	1068	1100

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.
not provided	Likely pathogenic (1)	criteria provided, single submitter	Sep 15, 2023	RCV003332447.1
Infantile neuroaxonal dystrophy	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 31, 2023	RCV003444385.4

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.
Likely pathogenic (Sep 15, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004039608.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant … (more) In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35911906, 35624904) (less)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Infantile neuroaxonal dystrophy (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV004171343.1 First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023	Comment: The missense c.967G>A (p.Val323Met) variant in PLA2G6 gene has been reported previously in compound heteroygous state in one individual with PLA2G6-associated neurodegeneration (Wan et al. … (more) The missense c.967G>A (p.Val323Met) variant in PLA2G6 gene has been reported previously in compound heteroygous state in one individual with PLA2G6-associated neurodegeneration (Wan et al. 2022). The p.Val323Met is reported with an allele frequency of 0.0006% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has not been reported to the ClinVar database. The amino acid change p.Val323Met in PLA2G6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 323 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS). (less)
Uncertain significance (Dec 31, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Infantile neuroaxonal dystrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004682522.1 First in ClinVar: Feb 28, 2024 Last updated: Feb 28, 2024	Publications: PubMed (3) PubMed: 32613234‚ 35624904‚ 35911906 Comment: This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 323 of the PLA2G6 protein (p.Val323Met). … (more) This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 323 of the PLA2G6 protein (p.Val323Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Parkinson disease and/or neurodegeneration with brain iron accumulation (PMID: 32613234, 35624904, 35911906). 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: 2581741). 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 not expected to disrupt PLA2G6 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)

Comment:

In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35911906, 35624904)

Comment:

The missense c.967G>A (p.Val323Met) variant in PLA2G6 gene has been reported previously in compound heteroygous state in one individual with PLA2G6-associated neurodegeneration (Wan et al. 2022). The p.Val323Met is reported with an allele frequency of 0.0006% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has not been reported to the ClinVar database. The amino acid change p.Val323Met in PLA2G6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Val at position 323 is changed to a Met changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).

Comment:

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 323 of the PLA2G6 protein (p.Val323Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of Parkinson disease and/or neurodegeneration with brain iron accumulation (PMID: 32613234, 35624904, 35911906). 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: 2581741). 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 not expected to disrupt PLA2G6 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel PLA2G6 Pathogenic Variants in Chinese Patients With PLA2G6-Associated Neurodegeneration.	Wan Y	Frontiers in neurology	2022	PMID: 35911906
Clinical Characterization and Founder Effect Analysis in Chinese Patients with Phospholipase A2-Associated Neurodegeneration.	Cheng HL	Brain sciences	2022	PMID: 35624904
The role of genetics in Parkinson's disease: a large cohort study in Chinese mainland population.	Zhao Y	Brain : a journal of neurology	2020	PMID: 32613234

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_003560.4(PLA2G6):c.967G>A (p.Val323Met)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...