rs374746113

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_003560.4(PLA2G6):c.386T>C(p.Leu129Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 1,611,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:3

Conservation

PhyloP100: 2.91

Publications

5 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:

ENSG00000279080 (HGNC:):

ENSG00000279080 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP5

Variant 22-38145477-A-G is Pathogenic according to our data. Variant chr22-38145477-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159768.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G6	NM_003560.4 link	c.386T>C	p.Leu129Pro	missense_variant	Exon 3 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.386T>C	p.Leu129Pro	missense_variant	Exon 3 of 17	1	NM_003560.4	ENSP00000333142.3		O60733-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000604

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:

0.000478

GnomAD2 exomes

AF:

0.0000446

AC:

AN:

246764

AF XY:

0.0000450

show subpopulations

Gnomad AFR exome

AF:

0.000696

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1459730

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

725984

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33456

American (AMR)

AF:

0.00

AC:

AN:

44366

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26010

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

85710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5480

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111458

Other (OTH)

AF:

0.00

AC:

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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

AF:

0.000171

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.000604

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68020

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000930

Hom.:

Bravo

AF:

0.000170

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Infantile neuroaxonal dystrophy

Pathogenic:2Uncertain:1

Feb 14, 2019

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PLA2G6 c.386T>C (p.Leu129Pro) variant is a missense variant that has been reported in one study, in which it is found in one presumably compound heterozygous individual with a second missense variant (Gitiaux et al. 2018). Control data are unavailable for this variant, which is reported at a frequency of 0.000571 in the African/African-American population of the Genome Aggregation Database. Based on the limited evidence, the p.Leu129Pro variant is classified as a variant of uncertain significance for infantile neuroaxonal dystrophy 1. -

Apr 01, 2022

Undiagnosed Diseases Network, NIH

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 129 of the PLA2G6 protein (p.Leu129Pro). This variant is present in population databases (rs374746113, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of PLA2G6-related conditions (PMID: 2939507, 29395073, 34307755, 35247231; internal data). 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: 159768). 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. -

not provided

Pathogenic:2

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PLA2G6: PM3:Strong, PM2, PS3:Supporting -

Jun 25, 2025

GeneDx

Significance:Likely 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: 26633542, 29395073, 29859652, 35247231, 35152491, 34307755, 39425167, 33528536) -

Neurodegeneration with brain iron accumulation

Pathogenic:1

Jun 20, 2024

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.386T>C (p.Leu129Pro) results in a non-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 9.2e-05 in 391476 control chromosomes, predominantly at a frequency of 0.00066 within the African or African-American subpopulation in the gnomAD database (v2.1 and v3.1). This frequency is somewhat lower than the maximum expected for a pathogenic variant in PLA2G6 causing Neurodegeneration with Brain Iron Accumulation (0.00085), allowing no conclusion about variant significance. The variant, c.386T>C, has been reported in the literature in compound heterozygous individuals affected with Neurodegeneration with Brain Iron Accumulation, infantile neuroaxonal dystrophy, or early-onset Parkinsonism with iron accumulation in the brain (e.g. Drecourt_2018, Gitiaux_2018, deOliveira_2021, Borja_2022) or in a patient with unspecified nervous system phenotype, where no variant in trans was specified (e.g. Retterer_2015). At least one publication reports experimental evidence evaluating an impact on protein function demonstrating iron overload and TfR1 dysregulation in patient derived fibroblasts (e.g. Drecourt_2018). The following publications have been ascertained in the context of this evaluation (PMID: 26633542, 29395073, 29859652, 34307755, 35247231). ClinVar contains an entry for this variant (Variation ID: 159768). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Inborn genetic diseases

Pathogenic:1

Sep 01, 2021

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.386T>C (p.L129P) alteration is located in exon 3 (coding exon 2) of the PLA2G6 gene. This alteration results from a T to C substitution at nucleotide position 386, causing the leucine (L) at amino acid position 129 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.01% (14/278142) total alleles studied. The highest observed frequency was 0.06% (14/24504) of African alleles. The p.L129P alteration has detected in the homozygous state and in trans with other PLA2G6 alterations in patients with features consistent with neurodegeneration with brain iron accumulation (Drecourt, 2018; Gitiaux, 2018; Ambry internal data). This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. -

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

Pathogenic:1

May 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Iron accumulation in brain

Uncertain:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PLA2G6-associated neurodegeneration

Uncertain:1

Jan 24, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Leu129Pro variant in PLA2G6 has been reported in 3 individuals with PLA2G6-associated neurodegeneration (PMID: 29859652, 34307755, 35247231) and has been identified in 0.06% (14/24504) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs374746113). 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#: 159768) and has been interpreted as likely pathogenic by GeneDx and Ambry Genetics and as a variant of uncertain significance by Illumina Laboratory Services (Illumina), Invitae, Genetic Services Laboratory (University of Chicago), and Women's Health and Genetics/Laboratory Corporation of America (LabCorp). Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the p.Leu129Pro variant is pathogenic (PMID: 35247231). In vitro functional studies provide some evidence that the p.Leu129Pro variant may slightly impact protein function (PMID: 29395073). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Leu129Pro variant is uncertain. ACMG/AMP Criteria applied: PS3_moderate, PM3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Benign

-0.085

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;.;.;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.60

LIST_S2

Uncertain

0.89

D;D;.;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.54

D;D;D;D

MetaSVM

Benign

-0.54

MutationAssessor

Uncertain

2.1

M;M;M;.

PhyloP100

2.9

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.4

D;D;D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.023

D;D;D;D

Sift4G

Benign

0.079

T;T;T;D

Polyphen

0.99

D;D;D;.

Vest4

0.65

MVP

0.78

MPC

0.97

ClinPred

0.52

GERP RS

5.3

Varity_R

0.62

gMVP

0.60

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over