NM_002662.5(PLD1):c.2098C>T (p.Arg700Cys) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 16, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001767548.3

Allele description [Variation Report for NM_002662.5(PLD1):c.2098C>T (p.Arg700Cys)]

NM_002662.5(PLD1):c.2098C>T (p.Arg700Cys)

Gene:

PLD1:phospholipase D1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3q26.31

Genomic location:

Preferred name:

NM_002662.5(PLD1):c.2098C>T (p.Arg700Cys)

HGVS:

NC_000003.12:g.171676732G>A
NG_029851.1:g.138763C>T
NM_001130081.3:c.1984C>T
NM_002662.5:c.2098C>TMANE SELECT
NP_001123553.1:p.Arg662Cys
NP_002653.1:p.Arg700Cys
NC_000003.11:g.171394522G>A
NM_002662.4:c.2098C>T

Protein change:

R662C

Links:

dbSNP: rs201247680

NCBI 1000 Genomes Browser:

rs201247680

Molecular consequence:

NM_001130081.3:c.1984C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002662.5:c.2098C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001998416	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Nov 13, 2019)	germline	clinical testing	Citation Link,
SCV004548919	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 16, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 33645542, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001998416

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Nov 13, 2019)

germline

clinical testing

Citation Link,

SCV004548919

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 16, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.

Lahrouchi N, Postma AV, Salazar CM, De Laughter DM, Tjong F, Piherová L, Bowling FZ, Zimmerman D, Lodder EM, Ta-Shma A, Perles Z, Beekman L, Ilgun A, Gunst Q, Hababa M, Škorić-Milosavljević D, Stránecký V, Tomek V, de Knijff P, de Leeuw R, Robinson JY, Burn SC, et al.

J Clin Invest. 2021 Mar 1;131(5). doi:pii: 142148. 10.1172/JCI142148.

PubMed [citation]

PMID:: 33645542
PMCID:: PMC7919725

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From GeneDx, SCV001998416.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV004548919.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 700 of the PLD1 protein (p.Arg700Cys). This variant is present in population databases (rs201247680, gnomAD 0.01%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 PLD1 protein function. ClinVar contains an entry for this variant (Variation ID: 1310434). This missense change has been observed in individual(s) with PLD1-related conditions (PMID: 33645542).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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