NM_003560.4:c.2222G>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1PM5PP5_Very_Strong

The NM_003560.4(PLA2G6):c.2222G>A(p.Arg741Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,401,016 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R741W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.83

Publications

39 publications found

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 Gene-Disease associations (from GenCC):

neurodegeneration with brain iron accumulation 2A
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
neurodegeneration with brain iron accumulation 2B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
PLA2G6-associated neurodegeneration
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive Parkinson disease 14
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet

PLA2G6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003560.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr22-38112559-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 265448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 22-38112558-C-T is Pathogenic according to our data. Variant chr22-38112558-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G6	NM_003560.4 link	c.2222G>A	p.Arg741Gln	missense_variant	Exon 16 of 17	ENST00000332509.8	NP_003551.2	O60733-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8 link	c.2222G>A	p.Arg741Gln	missense_variant	Exon 16 of 17	1	NM_003560.4	ENSP00000333142.3		O60733-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000903

AC:

AN:

154980

AF XY:

0.000145

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000337

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000421

AC:

AN:

1401016

Hom.:

Cov.:

AF XY:

0.0000520

AC XY:

AN XY:

691780

show subpopulations

African (AFR)

AF:

0.0000632

AC:

AN:

31650

American (AMR)

AF:

0.00

AC:

AN:

36354

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25248

East Asian (EAS)

AF:

0.00

AC:

AN:

35862

South Asian (SAS)

AF:

0.000464

AC:

AN:

79716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47014

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.0000166

AC:

AN:

1081454

Other (OTH)

AF:

0.0000344

AC:

AN:

58084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000337

Hom.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000461

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive Parkinson disease 14

Pathogenic:4

Sep 01, 2022

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.009%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.67; 3Cnet: 0.79). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000006203). A different missense change at the same codon (p.Arg741Trp) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265448). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 02, 2019

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A homozygous missense variation in exon 16 of the PLA2G6 gene that results in the amino acid substitution of Glutamine for Arginine at codon 741 was detected. The observed variation has not been reported in 1000 genomes and has a minor allele frequency of 0.02% in ExAc database. The in silico predictions of the variant are probably damaging by Polyphen-2 (HumDiv) and damaging by Mutation Taster2. The reference codon is conserved across mammals. The observed variant has previously been observed in patients with adult onset dystonia Parkinsonism (Pasian-Ruiz et al. 2009). In summary, the variant meets our criteria to be classified as likely pathogenic. -

Genomics England Pilot Project, Genomics England

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:3

Sep 13, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_strong, PM2_moderate, PM3_strong, PM5 -

Sep 27, 2021

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 21, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Functional analyses have not demonstrated a consistent damaging effect of this variant on protein activity (PMID: 20886109, 29108286); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18570303, 27268037, 29108286, 25601130, 31196701, 26668131, 20669327, 26196026, 24182522, 35499206, 35113461, 35016069, 31069529, 35329915, 35803092, 35152491, 34622992, 32183746, 35911906, 34520727, 32707456, 32860008, 35005075, 34758253, 20886109, 34272103, 33452780, 34365112) -

Neurodegeneration with brain iron accumulation 2B

Pathogenic:3

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed missense c.2222G>A (p.Arg741Gln) variant in PLA2G6 gene has been previously reported in homozygous state in multiple individuals affected with PLA2G6-related disorders (Paisán-Ruiz et al., 2010; Bohlega et al., 2016; Kumar et al., 2020). This variant has been observed to segregate with disease (Paisán-Ruiz et al., 2010). Functional studies showed that this variant is unable to maintain mitochondrial function and is defective in preventing mitochondrial dysfunction, ROS generation and activation of mitochondrial apoptotic pathway (Chiu et al., 2017). The p.Arg741Gln variant has been reported with allele frequency of 0.009% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). The amino acid change p.Arg741Gln in PLA2G6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 741 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2022

Solve-RD Consortium

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Infantile neuroaxonal dystrophy

Pathogenic:2

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 741 of the PLA2G6 protein (p.Arg741Gln). This variant is present in population databases (rs121908686, gnomAD 0.05%). This missense change has been observed in individuals with dystonia-parkinsonism (PMID: 18570303, 20669327, 26196026, 26668131, 27268037). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 6203). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PLA2G6 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Neurodegeneration with brain iron accumulation

Pathogenic:1

Feb 17, 2023

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PLA2G6 c.2222G>A (p.Arg741Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9e-05 in 154980 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PLA2G6 causing Neurodegeneration With Brain Iron Accumulation (9e-05 vs 0.00085), allowing no conclusion about variant significance. c.2222G>A has been reported in the literature in multiple individuals affected with dystonia-parkinsonism, with homozygous individuals reported and family members showing segregation of the variant with potential low penetrance (Paisan-Ruiz_2009, Bohlega_2016, Kumar_2020). These data indicate that the variant is very likely to be associated with disease. A different variant at the same amino acid has been reported as pathogenic by ClinVar (p.Arg741Trp). Six 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 likely pathogenic. -

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

Pathogenic:1

Feb 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.;.

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

D;D;.

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.58

D;D;D

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

1.4

L;.;.

PhyloP100

2.8

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.1

N;N;N

REVEL

Pathogenic

0.67

Sift

Benign

0.064

T;T;T

Sift4G

Benign

0.25

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.83

MVP

0.90

MPC

0.80

ClinPred

0.47

GERP RS

4.5

Varity_R

0.21

gMVP

0.34

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over