rs121908686

chr22-38112558-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PM5 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 2.83

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain 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 chr22-38112559-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id 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 [Likely_pathogenic]. Clinvar id is 6203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-38112558-C-T is described in Lovd as [Pathogenic]. Variant chr22-38112558-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLA2G6	NM_003560.4	c.2222G>A	p.Arg741Gln	missense_variant	16/17	ENST00000332509.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLA2G6	ENST00000332509.8	c.2222G>A	p.Arg741Gln	missense_variant	16/17	1	NM_003560.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000903 AC: 14 AN: 154980 Hom.: 0 AF XY: 0.000145 AC XY: 12 AN XY: 82836

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 SAS exome AF: 0.000518

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000337

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000421 AC: 59 AN: 1401016 Hom.: 0 Cov.: 31 AF XY: 0.0000520 AC XY: 36 AN XY: 691780

Gnomad4 AFR exome AF: 0.0000632

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000166

Gnomad4 OTH exome AF: 0.0000344

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000850 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000461 AC: 5

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive Parkinson disease 14 Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2009	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 02, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	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. -

Infantile neuroaxonal dystrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	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). 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 not expected to disrupt PLA2G6 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 27, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2020	Functional analyses have not demonstrated a consistent damaging effect of this variant on protein activity (Engel et al., 2010; Chiu et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32707456, 24182522, 31196701, 26196026, 20669327, 26668131, 18570303, 27268037, 25601130, 29108286, 20886109) -

Neurodegeneration with brain iron accumulation 2B Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.2222G>A (p.Arg741Gln) in PLA2G6 gene has been observed to segregate with dystonia-parkinsonism in several families (Davids M et al.,2015) . This variant has been reported to the ClinVar database as Pathogenic. The p.Arg741Gln variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.009033% is reported in gnomAD. 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. The variant is predicted to be damaging by PolyPhen2 and the residue is conserved across species. The amino acid change p.Arg741Gln in PLA2G6 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . -

Neurodegeneration with brain iron accumulation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Feb 17, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;.
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	0.58	A;A;A;A
PrimateAI	Benign	0.48	T
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	T
GERP RS		4.5
Varity_R		0.21
gMVP		0.34

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

LitVar

Other links and lift over

dbSNP: rs121908686; hg19: chr22-38508565;