rs1029766634

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_002667.5(PLN):c.53T>C(p.Ile18Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,612,926 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

PLN
NM_002667.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 6.64

Variant links:

Genes affected

PLN (HGNC:9080): (phospholamban) The protein encoded by this gene is found as a pentamer and is a major substrate for the cAMP-dependent protein kinase in cardiac muscle. The encoded protein is an inhibitor of cardiac muscle sarcoplasmic reticulum Ca(2+)-ATPase in the unphosphorylated state, but inhibition is relieved upon phosphorylation of the protein. The subsequent activation of the Ca(2+) pump leads to enhanced muscle relaxation rates, thereby contributing to the inotropic response elicited in heart by beta-agonists. The encoded protein is a key regulator of cardiac diastolic function. Mutations in this gene are a cause of inherited human dilated cardiomyopathy with refractory congestive heart failure, and also familial hypertrophic cardiomyopathy. [provided by RefSeq, Apr 2016]

PLN links:

CEP85L (HGNC:21638): (centrosomal protein 85 like) The protein encoded by this gene was identified as a breast cancer antigen. Nothing more is known of its function at this time. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

CEP85L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 30) in uniprot entity PPLA_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_002667.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.842

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLN	NM_002667.5 link	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 2	ENST00000357525.6	NP_002658.1	P26678Q5R352
CEP85L	NM_001042475.3 link	c.1020+6555A>G		intron_variant	Intron 3 of 12	ENST00000368491.8	NP_001035940.1	Q5SZL2-1Q3ZCQ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLN	ENST00000357525.6 link	c.53T>C	p.Ile18Thr	missense_variant	Exon 2 of 2	1	NM_002667.5	ENSP00000350132.5		P26678
CEP85L	ENST00000368491.8 link	c.1020+6555A>G		intron_variant	Intron 3 of 12	1	NM_001042475.3	ENSP00000357477.3		Q5SZL2-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1460738

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726748

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000386

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Dilated cardiomyopathy 1P

Uncertain:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 18 of the PLN protein (p.Ile18Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 28790153, 31705731; internal data). ClinVar contains an entry for this variant (Variation ID: 573774). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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. -

Cardiomyopathy

Uncertain:1

Jul 05, 2019

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1P;C3151265:Hypertrophic cardiomyopathy 18

Uncertain:1

Aug 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 18

Uncertain:1

Oct 15, 2018

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

PLN Ile18Thr has not been previously reported and is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We identified this variant in HCM proband with no family history of disease (Burns et al., 2017). In silico tools SIFT and MutationTaster predict this variant to be deleterious, but PolyPhen2 predicts it to be 'benign'. Based on this information we classify this as a variant of 'uncertain significance'. -

Cardiovascular phenotype

Uncertain:1

Nov 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I18T variant (also known as c.53T>C), located in coding exon 1 of the PLN gene, results from a T to C substitution at nucleotide position 53. The isoleucine at codon 18 is replaced by threonine, an amino acid with similar properties. This variant has been detected in individuals from hypertrophic cardiomyopathy cohorts and individuals tested for dilated cardiomyopathy (Lopes LR et al. J. Med. Genet., 2013;50:228-39; Chanavat V et al. Clin Chim Acta. 2016;453:80-5; Burns C et al. Circ Cardiovasc Genet, 2017;10). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

CardioboostCm

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.29

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.88

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

-0.014

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.025

Polyphen

0.059

Vest4

0.76

MVP

0.97

MPC

0.94

ClinPred

0.98

GERP RS

5.7

Varity_R

0.60

gMVP

0.76

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

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