rs149712244

Variant names:

• chr22-38116155-C-T
• rs149712244
• NM_003560.4:c.1799G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM5 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 7.33
• Publications: 7 publications found

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

ACMG classification

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

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-38116156-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 159748.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	c.1799G>A	p.Arg600Gln	missense_variant	Exon 13 of 17	ENST00000332509.8	NP_003551.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLA2G6	ENST00000332509.8	c.1799G>A	p.Arg600Gln	missense_variant	Exon 13 of 17	1	NM_003560.4	ENSP00000333142.3

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152196 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251096 AF XY: 0.0000442

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 22 AN: 1461626 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727116

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111900

Other (OTH) AF: 0.0000994 AC: 6 AN: 60386

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74344

African (AFR) AF: 0.000241 AC: 10 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.0000443 Hom.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Jul 06, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 29472584, 30619057, 20301718, 24745848, 34272103, 33619735, 2668131, 34168672, 18443314, 26668131, 20619503, 32613234, 37403138, 39184971, Kiel2024[Abstract], 36790591, 39425167) -

Jun 17, 2016

Knight Diagnostic Laboratories, Oregon Health and Sciences University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Infantile neuroaxonal dystrophy Pathogenic:2

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 13, 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 600 of the PLA2G6 protein (p.Arg600Gln). This variant is present in population databases (rs149712244, gnomAD 0.02%). 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. ClinVar contains an entry for this variant (Variation ID: 159748). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Neurodegeneration with brain iron accumulation 2B Pathogenic:2

Mar 06, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 15, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodegeneration with brain iron accumulation Pathogenic:1

Mar 21, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 17, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Pais&aacute;n-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

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PLA2G6-associated neurodegeneration Pathogenic:1

Jan 24, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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

Jun 06, 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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;.
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Pathogenic	3.6	H;.;.
PhyloP100		7.3
PrimateAI	Uncertain	0.53	T
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	D
GERP RS		4.6
Varity_R		0.93
gMVP		0.80
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs149712244; hg19: chr22-38512162;