rs149712244

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_003560.4(PLA2G6):c.1799G>A(p.Arg600Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R600W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 7.33

Variant links:

Genes affected

PLA2G6 (HGNC:9039): (phospholipase A2 group VI) The protein encoded by this gene is an A2 phospholipase, a class of enzyme that catalyzes the release of fatty acids from phospholipids. The encoded protein may play a role in phospholipid remodelling, arachidonic acid release, leukotriene and prostaglandin synthesis, fas-mediated apoptosis, and transmembrane ion flux in glucose-stimulated B-cells. Several transcript variants encoding multiple isoforms have been described, but the full-length nature of only three of them have been determined to date. [provided by RefSeq, Dec 2010]

PLA2G6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a domain PNPLA (size 184) in uniprot entity PLPL9_HUMAN there are 82 pathogenic changes around while only 3 benign (96%) in NM_003560.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-38116156-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1197568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

PP5

Variant 22-38116155-C-T is Pathogenic according to our data. Variant chr22-38116155-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38116155-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G6	NM_003560.4 linkuse as main transcript	c.1799G>A	p.Arg600Gln	missense_variant	13/17	ENST00000332509.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G6	ENST00000332509.8 linkuse as main transcript	c.1799G>A	p.Arg600Gln	missense_variant	13/17	1	NM_003560.4	P3	O60733-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251096

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461626

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.0000288

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 06, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jun 17, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35803092, 20619503, 33619735, 34272103, 29472584, 30619057, 20301718, 24745848, 2668131, 34168672, 36790591, 18443314, 26668131) -

Infantile neuroaxonal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R600Q in PLA2G6 (NM_003560.4) has been observed previously in individuals affected with Neuroaxonal Dystrophy (Paisán et al, 2012). Experimental studies reveal damaging effect (Davids et al, 2016). The p.R600Q variant is observed in 4/16,216 (0.0247%) alleles from individuals of African background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a small physicochemical difference between arginine and glutamine, which is not likely to impact secondary protein structure as these residues share similar properties.The p.R600Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 600 of PLA2G6 is conserved in all mammalian species. The nucleotide c.1799 in PLA2G6 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. The observed variant was also detected in heterozygous state in the proband's mother. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 05, 2023	For these reasons, this variant has been classified as Pathogenic. 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: 159748). This missense change has been observed in individual(s) with infantile neuroaxonal dystrophy (PMID: 20619503, 26668131, 33619735). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs149712244, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 600 of the PLA2G6 protein (p.Arg600Gln). -

Neurodegeneration with brain iron accumulation 2B

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 15, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 06, 2020	PLA2G6 c.1799G>A (rs149712244) is rare (<0.1%) in a large population dataset (gnomAD: 11/282490 total alleles; 0.0039%; no homozygotes). Four submitters in ClinVar classify this variant as either likely pathogenic or pathogenic (Variation ID: 159748). Three bioinformatics tools queried predict that this substitution would be deleterious. Additionally, bioinformatic analysis predicts that this variant would create a cryptic splice acceptor site in exon 13, which may cause abnormal gene splicing. However, this has not been confirmed experimentally to our knowledge. The arginine residue at this position is conserved across all species accessed. This variant in PLA2G6 has been reported previously in the homozygous state in a patient with infantile onset neuroaxonal dystrophy. We consider the c.1799G>A variant to be likely pathogenic. -

Neurodegeneration with brain iron accumulation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 21, 2023

Variant summary: PLA2G6 c.1799G>A (p.Arg600Gln) results in a conservative amino acid change located in the Patatin-like phospholipase domain (IPR002641) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251096 control chromosomes. c.1799G>A has been reported in the literature in multiple individuals affected with Neurodegeneration With Brain Iron Accumulation/PLA2G6-associated neurodegeneration (PLAN) disorders (example, PMID: 34272103, 33619735, 26668131, 20619503). 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. Nine 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. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2021

The c.1799G>A (p.R600Q) alteration is located in exon 13 (coding exon 12) of the PLA2G6 gene. This alteration results from a G to A substitution at nucleotide position 1799, causing the arginine (R) at amino acid position 600 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (11/282490) total alleles studied. The highest observed frequency was 0.02% (6/24928) of African alleles. This alteration has been reported in the homozygous and compound heterozygous states in individuals with PLA2G6-associated neurodegeneration (Davids, 2016; Paisán-Ruiz, 2012; Toth-Bencsik, 2021). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Infantile osteopetrosis with neuroaxonal dysplasia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The missense variant c.1799G>A(p.Arg600Gln) variant has been reported in individuals affected with Infantile neuroaxonal dystrophy 1 and related disorders(Coro et. al., 2012; Davids et. al., 2016; Paisán-Ruiz, Coro et al., 2012). This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The p.Arg600Gln variant is novel (not in any individuals) in 1000 Genomes and has allele frequency of 0.003894% in gnomAD database. The amino acid change p.Arg600Gln in PLA2G6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 600 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. For these reasons, this variant has been classified as Likely Pathogenic. -

PLA2G6-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2024

The PLA2G6 c.1799G>A variant is predicted to result in the amino acid substitution p.Arg600Gln. This variant has been reported in the compound heterozygous or homozygous state in patients with features consistent with PLA2G6-associated neurodegeneration disorder (Paisan-Ruiz et al. 2012. PubMed ID: 20619503; Davids et al. 2016. PubMed ID: 26668131; Bhardwaj et al. 2021. PubMed ID: 34272103). Another missense variant (c.1798C>T, p. Arg600Trp), which affects the same amino acid, has also been reported to be causative for PLA2G6-associated neurodegeneration with infantile and atypical childhood-onset (Illingworth et al. 2014. PubMed ID: 24745848). This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic. -

Iron accumulation in brain

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

PLA2G6-associated neurodegeneration

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 24, 2023

The p.Arg600Gln variant in PLA2G6 has been reported in 4 individuals with PLA2G6-associated neurodegeneration (PMID: 20619503, 34272103, 26668131, 33619735), and has been identified in 0.02% (6/24928) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs149712244). 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#: 159748) and has been interpreted as pathogenic and likely pathogenic by multiple submitters. Of the 4 affected individuals, 1 was a compound heterozygote that carried reported likely pathogenic variants in trans, and 2 were homozygotes, which increases the likelihood that the p.Arg600Gln variant is pathogenic (VariantID: 265448; PMID: 20619503, 34272103, 26668131). In vitro functional studies provide some evidence that the p.Arg600Gln variant may impact protein function (PMID: 26668131). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg600Trp, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 1197568). 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, PM5_supporting, PM3_strong, PS3_supporting (Richards 2015). -

Infantile neuroaxonal dystrophy;C1857747:Neurodegeneration with brain iron accumulation 2B;C2751842:Autosomal recessive Parkinson disease 14

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.36

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

D;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D;.

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

0.62

MutationAssessor

Pathogenic

3.6

H;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.93

MVP

0.91

MPC

0.95

ClinPred

1.0

GERP RS

4.6

Varity_R

0.93

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over