rs1004405095

Positions:

chr6-118558995-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM5

The NM_002667.5(PLN):c.74G>A(p.Arg25His) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,610,616 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

PLN
NM_002667.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 5.18

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 9 pathogenic changes around while only 0 benign (100%) in NM_002667.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-118558994-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 202040.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLN	NM_002667.5 linkuse as main transcript	c.74G>A	p.Arg25His	missense_variant	2/2	ENST00000357525.6
CEP85L	NM_001042475.3 linkuse as main transcript	c.1020+6534C>T		intron_variant		ENST00000368491.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLN	ENST00000357525.6 linkuse as main transcript	c.74G>A	p.Arg25His	missense_variant	2/2	1	NM_002667.5	P1
CEP85L	ENST00000368491.8 linkuse as main transcript	c.1020+6534C>T		intron_variant		1	NM_001042475.3	P1	Q5SZL2-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251160

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135720

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1458458

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

725830

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:

0.0000126

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 05, 2022	Identified in patients with HCM referred for genetic testing at GeneDx and in published literature (Walsh et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 28082330) -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 06, 2016	PLN p.Arg25His Given the lack of case data we consider this variant to be of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). We have seen this variant in a patient with a clinical diagnosis of HCM and was diagnosed with Fabry disease by a very likely disease-causing variant on the HCM panel. Testing was done by Invitae. The PLN variant has not been reported in the literature (as of 6/13/2016). Another variant affecting codon 25 has been reported by Dr. Hershberger's group. Liu et al., 2015 identified the R25C variant in a family with DCM and prominent arrhythmias. The PLN R25C variant came from the maternal side of the pedigree and a LMNA variant (c.607 G>A, p.Glu203Lys) came from the paternal side (previously reported in Parks et al., 2009). These variants showed incomplete segregation. The PLN variant segregated with cardiac disease in four of seven family members and the LMNA variant segregated with cardiac disease in four of seven family members. One person had both variants and presented at 47 with sudden cardiac arrest, then was diagnosed with DCM. His mother (palpitatations at 47, PVCs at 57, DCM at 71) and two of his sisters (one with LV dilation since 51, NSVT and ICD and the other with DCM at 45, NSVT and ICD) had the PLN variant. His father (AFib at 65, EF 45% at 82), uncle (DCM at 62, conduction disease, SCD), and another sister (DCM at 39, VT and ICD) had the LMNA variant. Functional studies were consistent with impaired calcium handling, suggesting pathogenicity. The Invitae report notes that the "sequence change replaces arginine with histidine at codon 25 of the PLN protein (p.Arg25His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine...Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies." There is no variation at codon 25 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of 6/13/2016). The mean and median coverages at that site in ExAC are greater than 80x. Approximately 95% of individuals have 50x coverage. -

Dilated cardiomyopathy 1P

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 06, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 25 of the PLN protein (p.Arg25His). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of PLN-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 410616). 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. This variant disrupts the p.Arg25 amino acid residue in PLN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25852082, 30847666; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2022

The p.R25H variant (also known as c.74G>A), located in coding exon 1 of the PLN gene, results from a G to A substitution at nucleotide position 74. The arginine at codon 25 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; (Harper AR et al. Nat Genet, 2021 02;53:135-142).). An alternate amino acid substitution at this codon, p.R25C, has been associated with a variety of cardiac phenotypes, including HCM, Brugada syndrome, and dilated cardiomyopathy (Lopes LR et al. Heart, 2015 Feb;101:294-301; Behr ER et al. Cardiovasc. Res., 2015 Jun;106:520-9; Liu GS et al. Cardiovasc. Res., 2015 Jul;107:164-74). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

CardioboostCm

Benign

0.032

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.42

MetaRNN

Uncertain

0.73

MetaSVM

Uncertain

0.47

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.027

Polyphen

0.98

Vest4

0.39

MutPred

0.79

Gain of methylation at K27 (P = 0.066);

MVP

0.99

MPC

1.3

ClinPred

0.94

GERP RS

5.6

Varity_R

0.46

gMVP

0.66

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