6-118558946-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_002667.5(PLN):c.25C>T(p.Arg9Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,452 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PLN
NM_002667.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.55

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 Pathogenic. Variant got 18 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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 6-118558946-C-T is Pathogenic according to our data. Variant chr6-118558946-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-118558946-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLN	NM_002667.5 link	c.25C>T	p.Arg9Cys	missense_variant	Exon 2 of 2	ENST00000357525.6	NP_002658.1	P26678Q5R352
CEP85L	NM_001042475.3 link	c.1020+6583G>A		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.25C>T	p.Arg9Cys	missense_variant	Exon 2 of 2	1	NM_002667.5	ENSP00000350132.5		P26678
CEP85L	ENST00000368491.8 link	c.1020+6583G>A		intron_variant	Intron 3 of 12	1	NM_001042475.3	ENSP00000357477.3		Q5SZL2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461452

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Aug 26, 2015

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg9Cys (c.25 C>T) The variant has been seen in at least one case of familial DCM with strong segregation and experimental data. Schmitt et al (2003) sequenced PLN in 20 individuals with familial DCM and found p.Arg9Cys in one of them. Five affected family members were available for genotyping and they all tested positive for this variant. Two of these individuals were fourth degree relatives to each other and several were third degree relatives to one another. The LOD score was 4.04. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging. The arginine at codon 9 is completely conserved across species, and neighboring amino acids are highly conserved. The PLN gene encodes phospholamban, a transmembrane phosphoprotein that inhibits the cardiac sarcoplasmic reticular Ca2 adenosine triphosphatase (SERCA2a) pump. Schmitt et al (2003) reported that transgenic mice with the p.Arg9Cys variant had heart failure and early death. In vitro studies showed constitutive inhibition of SERCA2a. There was a dominant negative effect in which the mutant protein trapped protein kinase A, which then failed to phosphorylate wildtype phospholamban. Calcium transients were prolonged and myocyte relaxation was delayed. In total the variant has not been seen in ~6600 published controls and individuals from publicly available population datasets. There is no variation at codon 9 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian and African American individuals (as of February 8th, 2013). Note that this dataset does not match the patient's ancestry. Interestingly, there is actually only one nonsynonymous variant in PLN listed in the entire ESP dataset (p.Ile14Arg) and that is present in only 1 of ~6500 individuals. p.Arg9Cys is listed in 1000 genomes, but only in reference to the dbSNP entry (rs111033559) which in turn points to a clinical OMIM submission. Thus it is not noted as present in general population samples in either of these databases. The variant was not observed in the following published control samples: Schmitt et al (2003) did not observe the variant in 100 reportedly normal individuals. -

Aug 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate this variant leads to a complete loss of function in both humans and transgenic mouse models (Schmitt et al., 2003; Gramolini et al., 2008; Schmitt et al., 2009; Ha et al., 2011; Ceholski et al., 2012a; Ceholski et al., 2012b); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23308118, 25593317, 23989713, 23302633, 15765133, 26917049, 25928149, 33978571, 30638982, 33265898, 32755452, 34199719, 32393743, 30012515, 32603312, 31325238, 27239561, 22427649, 22707725, 21282613, 26183555, 28102477, 18056057, 17010801, 25651173, 19139388, 29119312, 29447731, 29752948, 31402444, 35297759, 12610310) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dilated cardiomyopathy 1P

Pathogenic:2

Feb 15, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 9 of the PLN protein (p.Arg9Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 12610310, 25928149, 26917049; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13636). 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 disruptive. Experimental studies have shown that this missense change affects PLN function (PMID: 12610310, 21282613, 22427649, 22707725, 25593317). For these reasons, this variant has been classified as Pathogenic. -

Cardiomyopathy

Pathogenic:1

Dec 10, 2015

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary dilated cardiomyopathy

Pathogenic:1

Jun 03, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg9Cys variant in PLN has been reported in 2 individuals with DCM and seg regated with disease in 7 affected relatives from 1 family, including 3 obligate carriers (Schmitt 2003, Truszkowska 2015). Our laboratory has also identified o ne de novo occurrence of this variant in a child with ARVC. The p.Arg9Cys varian t was absent from large population studies, but is listed in dbSNP without frequ ency information (rs111033559). Transgenic mice expressing this variant develop DCM (Schmitt 2003, Schmitt 2009) and multiple functional studies support that th is variant has a severe impact on protein function (Gramolini 2007, Schmitt 2009 , Ha 2011, Ceholiski 2012a, Ceholiski 2012b, Abrol 2015). In summary, this varia nt meets our criteria to be classified as pathogenic for autosomal dominant DCM (http://www.partners.org/personalizedmedicine/LMM) based upon segregation studie s and functional evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

CardioboostCm

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.88

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-7.3

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.95

MutPred

0.83

Loss of MoRF binding (P = 3e-04);

MVP

0.99

MPC

1.5

ClinPred

1.0

GERP RS

4.8

Varity_R

0.77

gMVP

0.77

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