NM_001005242.3:c.1378+1G>C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001005242.3(PKP2):c.1378+1G>C variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000274 in 1,457,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001005242.3 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250730Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135578
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1457724Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3AN XY: 725404
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Arrhythmogenic right ventricular cardiomyopathy Pathogenic:3
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The c.1378+1G>C intronic variant of the PKP2 gene is located at the canonical donor splice site of intron 5. This variant has been reported in numerous (>15) individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 27194543, 23810894, 23671136, 20400443, 33968641, 28588093, 30830208, 34469894, 30677492, 24704780, 23810883, 25820315). This variant was also identified in the proband, mother and brother in a family, while the mother and brother were asymptomatic carriers (PMID: 33238575). An alteration at the same position, c.1378+1G>A, has also been reported to cause ARVC (PMID:18662195). In-silico computational prediction tools suggest that the c.1378+1G>C variant likely leads to donor loss and disturbs normal splicing, resulting in an absent of disrupted protein product (PMID: 16199547). Loss of function variants are known to be pathogenic for PKP2 gene (PMID: 23911551, 15489853, 24704780, 29038103, 34120153). Loss of function variants downstream of this variant are reported to be pathogenic in multiple individuals with ARVC/D (PMID: 26701096, 15489853, 17010805, 19358943, 20152563) and classified as pathogenic by several ClinVar submitters (ClinVar ID: 517335, 202019, 202035). This variant is found to be rare (1/250730; 0.000003988) in the general population database, gnomAD and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 45022). Therefore, the c.1378+1G>C variant in the PKP2 gene is classified as pathogenic. -
Arrhythmogenic right ventricular dysplasia 9 Pathogenic:2
This sequence change affects a donor splice site in intron 5 of the PKP2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKP2 are known to be pathogenic (PMID: 15489853, 17041889, 23911551). This variant is present in population databases (rs397516994, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (PMID: 18662195, 20400443, 31386562). ClinVar contains an entry for this variant (Variation ID: 45022). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
The PKP2 c.1378+1G>C variant has been reported in several individuals affected with ARVC (Costa S et al., PMID: 33238575; Fidler LM et al., PMID: 18662195; Fressart V et al., PMID: 20400443; Medeiros-Domingo A et al., PMID: 27194543; van Lint FHM et al., PMID: 31386562). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by six submitters and is only observed on 1/250,730 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Computational predictors indicate that this variant would alter splicing, evidence that correlates to an impact of this variant on PKP2 function. Additionally, another variant in the same nucleotide, c.1378+1G>A, has been described in an affected individual and is considered pathogenic (Fidler LM et al., PMID: 18662195, ClinVar Variation ID: 923177). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -
not provided Pathogenic:2
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Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease AND Non-canonical splice site variant demonstrated to result in loss-of-function (ref); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23671136, 27194543, 20400443, 23810894, 23810883, 30790397, 31386562, 31402444, 33238575, 30677492, 33232181) -
Cardiovascular phenotype Pathogenic:1
The c.1378+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 5 of the PKP2 gene. This mutation has been reported in individuals with arrhythmogenic right ventricular cardiomyopathy (ARVC) (Fressart V et al. Europace. 2010; 12:861-8; Bhonsale A et al. Circ Arrhythm Electrophysiol. 2013; 6:569-78; Medeiros-Domingo A et al. Europace, 2017 Jun;19:1063-1069; Hermida A et al. Eur J Heart Fail, 2019 06;21:792-800; Costa S et al. J Clin Med, 2020 Nov;9:). In addition, an alteration at the same position, c.1378+1G>A, has also been reported in association with ARVC (Fidler LM J et al. Cell Mol Med. 2009; 13:4219-28). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at