ClinVar Miner

Submissions for variant NM_001005242.3(PKP2):c.418T>A (p.Ser140Thr) (rs727503373)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000151661 SCV000199936 uncertain significance not specified 2013-09-27 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ser140Thr varia nt in PKP2 has been reported in the literature in one patient with DCM and was a bsent from controls (400 chromosomes, Elliott 2010). This variant has not been i dentified in large population studies (NHLBI Exome Sequencing Project). Computat ional analyses (biochemical amino acid properties, conservation, AlignGVGD, Poly Phen2, and SIFT) predict this variant may be tolerated. The wild-type residue at this position is not well conserved and the variant residue has been observed i n at least one distant species (Chicken), suggesting the mutation may be tolerat ed. Of note, another variant at the same position (Ser140Phe) has been reported in both individuals with ARVC as well as healthy controls and is thus unlikely to be a primary cause of disease, but a modifying role cannot be ruled out. In s ummary, more data are needed to determine the clinical significance of this vari ant.
Invitae RCV000707016 SCV000836094 uncertain significance Arrhythmogenic right ventricular cardiomyopathy, type 9 2019-12-06 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 140 of the PKP2 protein (p.Ser140Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in one individual affected with dilated cardiomyopathy (PMID: 20716751). ClinVar contains an entry for this variant (Variation ID: 164969). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756543 SCV000884379 uncertain significance not provided 2018-02-21 criteria provided, single submitter clinical testing The PKP2 c.418T>A; p.Ser140Thr variant (rs727503373) has been reported in a single individual with dilated cardiomyopathy (Elliott 2010). The p.Ser140Thr variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.0004% (identified on 1 out of 246,172 chromosomes) and is classified as a variant of unknown significance in ClinVar (ID: 164969). The serine at position 140 is moderately conserved, considering 8 species, and computational analyses of the effects of the p.Ser140Thr variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Another variant affecting the same codon, p.Ser140Phe, has also been reported in patients with arrhythmogenic right ventricular cardiomyopathy (Gerull 2004), and is enriched in ARVC patients compared to healthy controls (Christensen 2010); however, its prevalence in population genetic databases (0.4% in non-Finnish Europeans in gnomAD) and in healthy controls (Olfson 2015) suggests that it is at most disease modifying rather than pathogenic (Elliott 2010). Based on the available information, the clinical significance of the p.Ser140Thr variant cannot be determined with certainty.
Integrated Genetics/Laboratory Corporation of America RCV000151661 SCV000918018 uncertain significance not specified 2018-07-19 criteria provided, single submitter clinical testing Variant summary: PKP2 c.418T>A (p.Ser140Thr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246572 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.418T>A, has been reported in the literature in at least one affected individual with Arrhythmia (Elliott_2010). This report does not provide an unequivocal conclusion about association of the variant with Arrhythmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color RCV001177587 SCV001341824 uncertain significance Cardiomyopathy 2019-01-27 criteria provided, single submitter clinical testing

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