rs1004405095
Positions:
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
NM_002667.5 missense
Scores
5
10
4
Clinical Significance
Conservation
PhyloP100: 5.18
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]
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]
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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 | c.74G>A | p.Arg25His | missense_variant | 2/2 | ENST00000357525.6 | |
CEP85L | NM_001042475.3 | c.1020+6534C>T | intron_variant | ENST00000368491.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLN | ENST00000357525.6 | c.74G>A | p.Arg25His | missense_variant | 2/2 | 1 | NM_002667.5 | P1 | |
CEP85L | ENST00000368491.8 | c.1020+6534C>T | intron_variant | 1 | NM_001042475.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152158Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251160Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135720
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GnomAD4 exome AF: 0.0000110 AC: 16AN: 1458458Hom.: 0 Cov.: 28 AF XY: 0.0000152 AC XY: 11AN XY: 725830
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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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
CardioboostCm
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Gain of methylation at K27 (P = 0.066);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at