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Fetal anomalies

Gene: PLD1

Amber List (moderate evidence)
PLD1 (phospholipase D1)
EnsemblGeneIds (GRCh38): ENSG00000075651
EnsemblGeneIds (GRCh37): ENSG00000075651
OMIM: 602382, Gene2Phenotype
PLD1 is in 4 panels

5 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

I don't know

The rating of this gene has been updated to amber following NHS Genomic Medicine Service approval.
Created: 25 Feb 2025, 11:15 a.m. | Last Modified: 25 Feb 2025, 11:15 a.m.
Panel Version: 5.78
This gene and phenotype were reviewed during meetings between November 2024 & January 2025. The meetings included representatives of the Central & South and North Thames R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Stephanie Allen, Natalie Bibb, and Sarah Graham (Central & South GLH), Natalie Chandler and Elizabeth Scotchman (North Thames GLH), and Sunayna Best, Anna De Burca, Natalie Canham, Samantha Doyle, Alice Gardham, Victoria Harrison, Esther Kinning, Sahar Mansour, Soo-Mi Park, and Elizabeth Wall (R21 Clinical Oversight Group).
Created: 20 Feb 2025, 9:40 p.m. | Last Modified: 20 Feb 2025, 9:40 p.m.
Panel Version: 5.16
Created: 20 Feb 2025, 9:40 p.m.
Last Modified: 20 Feb 2025, 9:40 p.m.
Panel version: 5.78

Sarah Graham (West Midlands Regional Genetics Laboratory, Birmingham Women's and Children’s NHS Foundation Trust)

I don't know

No longer green on any other panel as has been downgraded - see review on paediatric cardiomyopathy panel highlighting limitations of the main paper proposing a link between biallelic PLD1 variants and cardiac phenotypes (PMID: 33645542). Agree with this review that some of the published PLD1 variants are likely to be spurious associations in view of high MAF and homozygotes in gnomAD. However, of the 21 families in this paper, 3 (families O, Q and T) have biallelic likely loss-of-function variants (but not identical phenotypes - families O and Q valvular defects; family T dilated cardiomyopathy). Hearts of PLD1 knockout mice showed tricuspid regurgitation, right atrial enlargement, and increased flow velocity, narrowing and thickened leaflets of the pulmonic valve (PMID: 27799408). No homozygous LoF variants in gnomAD. Remains possible that biallelic PLD1 LoF variants are associated with heart abnormalities.
Created: 20 Feb 2025, 9:35 p.m. | Last Modified: 20 Feb 2025, 9:35 p.m.
Panel Version: 5.15

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cardiac valvular dysplasia 1, MIM#212093

Publications

Created: 20 Feb 2025, 9:35 p.m.
Last Modified: 20 Feb 2025, 9:35 p.m.
Panel version: 5.15

Rhiannon Mellis (Great Ormond Street Hospital)

Green List (high evidence)

This gene and phenotype were reviewed during a meeting on 21st July 2022 between representatives of the North Thames and Central & South R21 testing GLHs.
Clinical review and curation was performed by Lyn Chitty, Alison Male, Rhiannon Mellis (North Thames GLH), and Stephanie Allen, Denise Williams, Esther Kinning and Anna de Burca (Central & South GLH).

Outcome of review: Note already recommended to go Green at next update. Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.

Details of review: In addition to the case series noted in the previous review by Suzanne Drury, also adding 2 fetal cases (sibs) in Qiao et al 2021 (PMID: 33142350) - both had Endocardial fibroelastosis, one had PS, mitral regurgitation and the other had aortic atresia. (The fibroelastosis is a novel phenotype not previously reported with PLD1)
Created: 1 Aug 2022, 5:33 p.m. | Last Modified: 1 Aug 2022, 5:33 p.m.
Panel Version: 1.880

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cardiomyopathy; Congenital heart malformations

Publications

Created: 1 Aug 2022, 5:33 p.m.
Last Modified: 1 Aug 2022, 5:33 p.m.
Panel version: 1.880

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

This gene was previously downgraded from Green to Amber following review by Jesse Hayesmoore highlighting the presence of homozygotes in population databases, including some patient variants. However, additional cases have continued to be published albeit often with limited information and no extensive functional studies. This gene-condition has been reviewed by multiple resources including:

- ClinGen: definitive (classified on 12-02-2024) - https://search.clinicalgenome.org/CCID:008897
- G2P: definitive (classified on 19-02-2025) - https://www.ebi.ac.uk/gene2phenotype/lgd/G2P03704
- PanelApp Australia: green on multiple panels - https://panelapp-aus.org/panels/entities/PLD1
- OMIM (last updated on 30-09-2022) - https://www.omim.org/entry/212093

Given the classification on Genomics England PanelApp currently conflicts with multiple other resources, this gene will be flagged for additional expert review during the next GMS panel release.
Created: 20 Oct 2025, 2:14 p.m. | Last Modified: 20 Oct 2025, 2:14 p.m.
Panel Version: 6.103
Comment on phenotypes: Updated OMIM:212093 phenotype from 'Cardiac valvular defect, developmental' to 'Cardiac valvular dysplasia 1' (accessed on 20-10-2025)
Created: 20 Oct 2025, 1:47 p.m. | Last Modified: 20 Oct 2025, 1:47 p.m.
Panel Version: 6.102
Additional cases reported (not reviewed previously):

- PMID: 38171566 - based on the abstract (translated from Chinese, full-text not available) a fetus with generalized edema, complex cardiac malformation, abdominal effusion, and enhanced intestinal and renal parenchymal echoes was identified with compound heterozygous variants (c.1460G>A (p.W487*); c.2977C>T (p.R993*)) in the PLD1 gene. No functional studies mentioned.

- PMID: 39553471 - a fetus with compound heterozygous variants (c.1937G>C (p.G646A); c.1062-59A>G) was found with congenital heart disease including pulmonary atresia, regurgitation and tricuspid valve dysplasia. In silico analysis of c.1062-59A>G indicated the variant affected splicing, and subsequent RT-PCR and TA clone sequencing revealed a 76-bp intron retention and skipping of exon 11, causing a frameshift and premature stop codon in PLD1. Both variants were classified as VUS according to ACMG guidelines.

- PMID: 39681445 - title 'A case of cardiac valvular dysplasia combined with dilated cardiomyopathy caused by a homozygous nonsense variant in PLD1' indicates there is another case of cardiomyopathy linked to this gene. However, the article and abstract are in Chinese and therefore cannot be curated further.
Created: 20 Oct 2025, 1:45 p.m. | Last Modified: 20 Oct 2025, 1:45 p.m.
Panel Version: 6.101
Comment on list classification: This Green gene was signed off in Mar 2023 but now flagging for another review by the GMS specialist group in the context of the conflicting Red review by Jesse Hayesmoore (Oxford Regional Genetics Laboratory) to determine whether this gene should be downgraded.
Created: 23 Apr 2024, 1:17 p.m. | Last Modified: 23 Apr 2024, 1:18 p.m.
Panel Version: 3.157
Copied review from Paediatric or syndromic cardiomyopathy (749) v3.43 panel:

Jesse Hayesmoore (Oxford Regional Genetics Laboratory)
Red List (low evidence)

"On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease (not cardiomyopathy) have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines."
Created: 31 Jan 2024, 12:04 p.m. | Last Modified: 31 Jan 2024, 12:17 p.m
Created: 23 Apr 2024, 1:06 p.m. | Last Modified: 23 Apr 2024, 1:06 p.m.
Panel Version: 3.156
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.
Created: 30 Jan 2023, 4:26 p.m. | Last Modified: 30 Jan 2023, 4:26 p.m.
Panel Version: 2.10
Comment on list classification: New gene added by Suzanne Drury (Congenica). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. There is enough evidence to support a fetally-relevant gene-disease association. This gene should be rated Green at the next review.
Created: 19 May 2021, 3:13 p.m. | Last Modified: 19 May 2021, 3:13 p.m.
Panel Version: 1.654

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cardiac valvular dysplasia 1, OMIM:212093

Publications

Created: 19 May 2021, 3:13 p.m.
Last Modified: 23 Apr 2024, 1:18 p.m.
Panel version: 6.103

Suzanne Drury (Congenica Ltd)

Green List (high evidence)

PMID 33645542 identified 30 patients from 21 unrelated families of different ancestries with biallelic PLD1 variants. All 30 patients were diagnosed with severe congenital heart disease or
cardiomyopathy at the fetal or neonatal stage. PLD1 can also cause neonatal cardiomyopathy in the absence of congenital heart defects.
Sources: Literature
Created: 9 Apr 2021, 9:47 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
HP:0001654; HP:0001627; HP:0001638

Publications

Created: 9 Apr 2021, 9:47 a.m.

Panel version: 1.637

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • NHS GMS
Phenotypes
  • Cardiac valvular dysplasia 1, OMIM:212093
  • Congenital heart malformations
Tags
Q3_25_promote_green Q3_25_expert_review
OMIM
602382
Clinvar variants
Variants in PLD1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

20 Oct 2025, Gel status: 2

Added Tag, Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_25_promote_green tag was added to gene: PLD1. Tag Q3_25_expert_review tag was added to gene: PLD1.

20 Oct 2025, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: PLD1 were set to 33645542; 27799408; 33142350

20 Oct 2025, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental, OMIM:212093; Cardiomyopathy; Congenital heart malformations to Cardiac valvular dysplasia 1, OMIM:212093; Congenital heart malformations

25 Feb 2025, Gel status: 2

Removed Tag, Removed Tag, Removed Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q1_25_ demote_amber was removed from gene: PLD1. Tag Q1_25_ NHS_review was removed from gene: PLD1. Tag Q2_24_expert_review was removed from gene: PLD1.

25 Feb 2025, Gel status: 2

Added New Source, Status Update

Achchuthan Shanmugasundram (Genomics England Curator)

Source Expert Review Amber was added to PLD1. Rating Changed from Green List (high evidence) to Amber List (moderate evidence)

21 Feb 2025, Gel status: 3

Removed Tag, Added Tag, Added Tag

Achchuthan Shanmugasundram (Genomics England Curator)

Tag Q2_24_demote_red was removed from gene: PLD1. Tag Q1_25_ demote_amber tag was added to gene: PLD1. Tag Q1_25_ NHS_review tag was added to gene: PLD1.

20 Feb 2025, Gel status: 3

Set publications

Achchuthan Shanmugasundram (Genomics England Curator)

Publications for gene: PLD1 were updated from 27799408; 33645542; 33142350 to 33645542; 27799408; 33142350

23 Apr 2024, Gel status: 3

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: pld1 has been classified as Green List (High Evidence).

23 Apr 2024, Gel status: 3

Added Tag, Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q2_24_demote_red tag was added to gene: PLD1. Tag Q2_24_expert_review tag was added to gene: PLD1.

30 Jan 2023, Gel status: 3

Removed Tag, Removed Tag

Arina Puzriakova (Genomics England Curator)

Tag Q2_21_rating was removed from gene: PLD1. Tag Q3_22_NHS_review was removed from gene: PLD1.

30 Jan 2023, Gel status: 3

Added New Source, Added New Source, Status Update

Arina Puzriakova (Genomics England Curator)

Source Expert Review Green was added to PLD1. Source NHS GMS was added to PLD1. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)

9 Aug 2022, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: PLD1 were changed from Cardiac valvular defect, developmental, OMIM:212093 to Cardiac valvular defect, developmental, OMIM:212093; Cardiomyopathy; Congenital heart malformations

9 Aug 2022, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: PLD1 were set to 27799408; 33645542

9 Aug 2022, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q3_22_NHS_review tag was added to gene: PLD1.

19 May 2021, Gel status: 2

Added Tag

Arina Puzriakova (Genomics England Curator)

Tag Q2_21_rating tag was added to gene: PLD1.

19 May 2021, Gel status: 2

Set publications

Arina Puzriakova (Genomics England Curator)

Publications for gene: PLD1 were set to 33645542

19 May 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: pld1 has been classified as Amber List (Moderate Evidence).

19 May 2021, Gel status: 0

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: PLD1 were changed from HP:0001654; HP:0001627; HP:0001638 to Cardiac valvular defect, developmental, OMIM:212093

9 Apr 2021, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Suzanne Drury (Congenica Ltd)

gene: PLD1 was added gene: PLD1 was added to Fetal anomalies. Sources: Literature Mode of inheritance for gene: PLD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PLD1 were set to 33645542 Phenotypes for gene: PLD1 were set to HP:0001654; HP:0001627; HP:0001638 Review for gene: PLD1 was set to GREEN