rs121908680

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_003560.4(PLA2G6):c.2370T>G(p.Tyr790*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,609,764 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 (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

PLA2G6
NM_003560.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24U:1

Conservation

PhyloP100: 0.103

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 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 22-38112212-A-C is Pathogenic according to our data. Variant chr22-38112212-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38112212-A-C is described in Lovd as [Pathogenic]. Variant chr22-38112212-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLA2G6	NM_003560.4 link	c.2370T>G	p.Tyr790*	stop_gained	Exon 17 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.2370T>G	p.Tyr790*	stop_gained	Exon 17 of 17	1	NM_003560.4	ENSP00000333142.3		O60733-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000822

AC:

AN:

243312

Hom.:

AF XY:

0.0000759

AC XY:

AN XY:

131812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000148

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000337

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000128

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000129

AC:

188

AN:

1457606

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

724812

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000113

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000702

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000150

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.0000982

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000495

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:24Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Infantile neuroaxonal dystrophy

Pathogenic:10

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The stop gained c.2370T>G (p.Y790*) in PLA2G6 (NM_003560.4) has been observed in the homozygous and compound heterozygous state in individuals affected with PLA2G6-related conditions (Morgan NV et al; Blake RB et al). Experimental studies have shown that this variant disrupts PLA2G6 enzymatic activity in vitro (Engel LA et al). The observed variant has been reported to ClinVar as Conflicting Interpretations Of Pathogenicity. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic -

Jul 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 30, 2017

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Sep 01, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as disease-causing and was found twice in our laboratory with another variant in affected individuals: a 2-year-old male with regression, hearing loss, hypotonia, failure to thrive, cerebellar atrophy, vision loss; a 5-year-old female with regression, dystonia, epilepsy, microcephaly, failure to thrive, cerebellar atrophy. Heterozygotes would be expected to be asymptomatic carriers. -

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 18, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 27, 2018

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Tyr790*) in the PLA2G6 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the PLA2G6 protein. This variant is present in population databases (rs121908680, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with clinical features of PLA2G6-related conditions (PMID: 16783378, 27378808; internal data). ClinVar contains an entry for this variant (Variation ID: 6195). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PLA2G6 function (PMID: 20886109). For these reasons, this variant has been classified as Pathogenic. -

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:3

Oct 22, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PLA2G6: PVS1, PM2 -

Mar 30, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies demonstrate that this variant significantly impairs catalytic activity of the PLA2G6 protein (Engel et al., 2010); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 17 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 18359254, 20886109, 16783378, 27378808, 28600779, 24800972, 18443314, 24847269, 18570303, 24745848, 30537300, 30340910, 20619503, 33101984, 31589614) -

PLA2G6-associated neurodegeneration

Pathogenic:3

Jan 24, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Tyr790Ter variant in PLA2G6 has been reported in >10 individuals with PLA2G6-associated neurodegeneration (PMID: 33101984, 18359254, 18799783, 27378808, 30293248, 28716262, 16783378, 28600779, 30340910, 32860008, 34602496, 35122944, Miryounesi 2018, 30868093, 34622992, 30537300, 33619735, 29859652, Silva 2014), segregated with disease in 2 affected relatives from 2 families (PMID: 28716262, 31196701), and has been identified in 0.02% (19/125174) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121908680). 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#: 6195) and has been interpreted as pathogenic and likely pathogenic by multiple submitters, as well as a variant of uncertain significance by the Institute for Medical Genetics and Human Genetics (Charit√© - Universit√§tsmedizin Berlin). Of the 26 affected individuals, 12 of those were homozygotes, and 5 were compound heterozygotes that carried reported likely pathogenic variants in trans or with unknown phase, which increases the likelihood that the p.Tyr790Ter variant is pathogenic (Variant ID: 159741, 265448; PMID: 33101984, 18359254, 18799783, 27378808, 30293248, 28716262, 16783378, 28600779, 30340910, 32860008, 34602496, 35122944, Miryounesi 2018). In vitro functional studies provide some evidence that the p.Tyr790Ter variant impacts protein function (PMID: 20886109, 35122944). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 790. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the PLA2G6 gene is an established disease mechanism in autosomal recessive PLA2G6-associated neurodegeneration. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive PLA2G6-associated neurodegeneration. ACMG/AMP Criteria applied: PVS1_moderate, PM3_very-strong, PP1, PS3_moderate (Richards 2015). -

Oct 18, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PLA2G6 c.2370T>G (p.Tyr790Ter) variant is a stop-gained variant and has been reported in at least eight studies in a total of 11 probands with PLA2G6-associated neurodegeneration, including in at least five in a homozygous state, in five in a compound heterozygous state, and in one in a heterozygous state (Morgan et al. 2006; Carrilho et al. 2008; Gregory et al. 2008; Pinto et al. 2010; Paisan-Ruiz 2012; Illingworth et al. 2014; Blake et al. 2016; Erro et al. 2016). Of note, another variant, c.2370_2371delTG, which also results in p.Tyr790Ter, has been reported in both a homozygous and compound heterozygous state in other probands. Control data are not available for the p.Tyr790Ter variant, which is reported at a frequency of 0.000148 in the Latino from the Genome Aggregation Database. In vitro studies examining the catalytic function of the p.Tyr790Ter variant demonstrated <10% phospholipase activity compared to wildtype in the presence of two different substrates (Engel et al. 2010). Based on the collective evidence, the p.Tyr790Ter variant is classified as pathogenic for PLA2G6-associated neurodegeneration. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with PLA2G6-associated neurodegeneration (MONDO#0017998). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Intra-familial variability has been reported (PMID: 34622992). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 25 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in several homozygotes and compound heterozygotes affected with PLA2G6-associated neurodegeneration (PMID: 28542792). (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Neurodegeneration with brain iron accumulation 2B

Pathogenic:2

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The stop gained variant c.2370T>G (p.Tyr790Ter) in PLA2G6 gene has been reported in at least eight studies in a total of 11 probands with PLA2G6-associated neurodegeneration (Morgan NV et.al.,2006). Functional studies demonstrate that this variant significantly impairs catalytic activity of the PLA2G6 protein (Engel et al., 2010). This variant has been reported to the ClinVar database as Pathogenic.The variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.009102% is reported in gnomAD. The nucleotide change in PLA2G6 is predicted as conserved by PhyloP across 100 vertebrates.For these reasons, this variant has been classified as Pathogenic -

Jan 01, 2018

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 16783378, 27378808, 20886109] -

Neurodegeneration with brain iron accumulation

Pathogenic:1

May 24, 2022

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.2370T>G (p.Tyr790X) located in the last exon results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.2e-05 in 243312 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PLA2G6 (8.2e-05 vs 0.00085), allowing no conclusion about variant significance. c.2370T>G has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with features of PLA2G6-associated neurodegeneration (PLAN), predominantly as infantile neuroaxonal dystrophy (INAD) (example, Carrilho_2008, Gregory_2008, Darling_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal Phospholipase and lysophospholipase catalytic activities in-vitro (example, Engel_2010). Twelve 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

Jun 20, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PLA2G6-related disorder

Pathogenic:1

Sep 23, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PLA2G6 c.2370T>G variant is predicted to result in premature protein termination (p.Tyr790*). This variant has been reported in the homozygous or compound heterozygous state in multiple individuals with infantile neuroaxonal dystrophy or neurodegeneration with brain iron accumulation (see for example, Gitiaux et al. 2018. PubMed ID: 29859652; AlBanji et al. 2020. PubMed ID: 33101984; Table S1, Brunet et al. 2021. PubMed ID: 33619735). An in vitro experimental study suggests this variant decreases enzymatic activity to less that 10% of wildtype activity (Figure 3, Engel et al. 2010. PubMed ID: 20886109). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-38508219-A-C). Nonsense variants in PLA2G6 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Iron accumulation in brain

Pathogenic:1

Mar 17, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Abnormality of the nervous system

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autism;C0036572:Seizure

Uncertain:1

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

We were able to detect the known pathogenic mutation c.2370T>G in the PLA2G6 gene in the patient in a heterozygous state. The variant was also detected in the mother of the patient in heterozygous state. The PLA2G6 gene codes for phospholipase A2 of group 6 (MIM *603604). Biallelic pathogenic sequence variants in PLA2G6 have been described with three clinical manifestations of autosomal recessively inherited PLA2G6-associated neurodegeneration: 1) infantile neuroaxonal dystrophy (INAD, MIM: 256600), 2) neurodegeneration with iron accumulation in the brain (NBIA, MIM: 610217) and 3) PLA2G6-dependent dystonia parkinsonism (MIM: 612953). Clinical symptoms include psychomotor regression, symmetrical pyramidal trajectory signs, pronounced trunk hypotension, spastic quadriplegia, visual disturbances and dementia. The clinical course may be variable. The above variation leads to the formation of a premature stop codon and thus most likely to the premature termination of protein biosynthesis. The variant has already been reported in numerous patients in homozygous or compound-heterozygous condition (HGMD: CM063050). The sequence variant is listed in gnomAD 25x in heterozygous state and occurs in the European subpopulation with an allele frequency of 0.015%. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Benign

0.0057

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.74

Vest4

0.73

GERP RS

-5.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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