VCV002412647.2 - ClinVar

NM_003560.4(PLA2G6):c.1472T>G (p.Leu491Arg)

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.

(2)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_003560.4(PLA2G6):c.1472T>G (p.Leu491Arg)

Variation ID: 2412647 Accession: VCV002412647.2

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 22q13.1 22: 38123214 (GRCh38) [ NCBI UCSC ] 22: 38519221 (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	Feb 8, 2023	Feb 14, 2024	Sep 18, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003560.4:c.1472T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003551.2:p.Leu491Arg	missense
NM_001004426.3:c.1310T>G	NP_001004426.1:p.Leu437Arg	missense
NM_001199562.3:c.1310T>G	NP_001186491.1:p.Leu437Arg	missense
NM_001349864.2:c.1472T>G	NP_001336793.1:p.Leu491Arg	missense
NM_001349865.2:c.1310T>G	NP_001336794.1:p.Leu437Arg	missense
NM_001349866.2:c.1310T>G	NP_001336795.1:p.Leu437Arg	missense
NM_001349867.2:c.938T>G	NP_001336796.1:p.Leu313Arg	missense
NM_001349868.2:c.794T>G	NP_001336797.1:p.Leu265Arg	missense
NM_001349869.2:c.776T>G	NP_001336798.1:p.Leu259Arg	missense
NC_000022.11:g.38123214A>C
NC_000022.10:g.38519221A>C
NG_007094.3:g.96565T>G
LRG_1015:g.96565T>G
LRG_1015t1:c.1472T>G	LRG_1015p1:p.Leu491Arg

... more HGVS ... less HGVS

Protein change

L313R, L437R, L259R, L265R, L491R

Other names

NM_001004426.3:c.1310T>G

Canonical SPDI

NC_000022.11:38123213:A:C

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.
PLA2G6-associated neurodegeneration	Uncertain significance (1)	criteria provided, single submitter	Jan 24, 2023	RCV002789940.2
Infantile neuroaxonal dystrophy	Uncertain significance (1)	criteria provided, single submitter	Sep 18, 2023	RCV003507473.2

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.
Uncertain significance (Jan 24, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	PLA2G6-associated neurodegeneration (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV003760996.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Comment: The p.Leu491Arg variant in PLA2G6 has been reported in 1 individual, in the compound heterozygous state, with PLA2G6-associated neurodegeneration (PMID: 16783378) and has been identified … (more) The p.Leu491Arg variant in PLA2G6 has been reported in 1 individual, in the compound heterozygous state, with PLA2G6-associated neurodegeneration (PMID: 16783378) and has been identified in 0.004% (1/25414) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1449537489). 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. 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, the clinical significance of the p.Leu491Arg variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PP3(Richards 2015). (less)
Uncertain significance (Sep 18, 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: SCV004285734.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 16783378‚ 34272103 Comment: 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 … (more) 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. This variant disrupts the p.Leu491 amino acid residue in PLA2G6. Other variant(s) that disrupt this residue have been observed in individuals with PLA2G6-related conditions (PMID: 16783378, 34272103), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 2412647). This missense change has been observed in individual(s) with infantile neuroaxonal dystrophy (PMID: 16783378). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 491 of the PLA2G6 protein (p.Leu491Arg). (less)

Comment:

The p.Leu491Arg variant in PLA2G6 has been reported in 1 individual, in the compound heterozygous state, with PLA2G6-associated neurodegeneration (PMID: 16783378) and has been identified in 0.004% (1/25414) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1449537489). 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. 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, the clinical significance of the p.Leu491Arg variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PP3(Richards 2015).

Comment:

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. This variant disrupts the p.Leu491 amino acid residue in PLA2G6. Other variant(s) that disrupt this residue have been observed in individuals with PLA2G6-related conditions (PMID: 16783378, 34272103), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 2412647). This missense change has been observed in individual(s) with infantile neuroaxonal dystrophy (PMID: 16783378). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 491 of the PLA2G6 protein (p.Leu491Arg).

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
Neurodegeneration with brain iron accumulation: Characterization of clinical, radiological, and genetic features of pediatric patients from Southern India.	Bhardwaj NK	Brain & development	2021	PMID: 34272103
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 this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_003560.4(PLA2G6):c.1472T>G (p.Leu491Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...