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

gnomAD frequency: 0.00002  dbSNP: rs727503373

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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 dysplasia 9	2023-09-29	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 140 of the PKP2 protein (p.Ser140Thr). This variant is present in population databases (rs727503373, gnomAD 0.0009%). This missense change has been observed in individual(s) 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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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 Diagnostics, LLC DBA Color Health	RCV001177587	SCV001341824	uncertain significance	Cardiomyopathy	2024-01-17	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 140 of the PKP2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with dilated cardiomyopathy (PMID: 20716751). This variant has been identified in 2/251368 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV000756543	SCV001820316	uncertain significance	not provided	2021-01-21	criteria provided, single submitter	clinical testing	Reported in a patient with DCM (Elliott et al., 2010); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 164969; Landrum et al., 2016) This variant is associated with the following publications: (PMID: 20716751)
Ambry Genetics	RCV002326868	SCV002630792	uncertain significance	Cardiovascular phenotype	2020-12-04	criteria provided, single submitter	clinical testing	The p.S140T variant (also known as c.418T>A), located in coding exon 3 of the PKP2 gene, results from a T to A substitution at nucleotide position 418. The serine at codon 140 is replaced by threonine, an amino acid with similar properties. This variant has been detected in a dilated cardiomyopathy cohort; however, clinical details were limited (Elliott P et al. Circ Cardiovasc Genet, 2010 Aug;3:314-22). This amino acid position is not well conserved in available vertebrate species, and threonine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV000707016	SCV002792285	uncertain significance	Arrhythmogenic right ventricular dysplasia 9	2021-10-13	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000756543	SCV001740616	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000756543	SCV001972082	uncertain significance	not provided		no assertion criteria provided	clinical testing