Submissions for variant NM_020433.5(JPH2):c.1204G>A (p.Glu402Lys)

gnomAD frequency: 0.00038  dbSNP: rs147407445

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000168201	SCV000218866	uncertain significance	Hypertrophic cardiomyopathy	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 402 of the JPH2 protein (p.Glu402Lys). This variant is present in population databases (rs147407445, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with JPH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 188245). 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. 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000217886	SCV000271850	uncertain significance	not specified	2015-04-01	criteria provided, single submitter	clinical testing	The p.Glu402Lys variant in JPH2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 38/66478 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs147407445). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Glu402Lys variant is uncertain.
GeneDx	RCV000217886	SCV000490572	uncertain significance	not specified	2016-06-08	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the JPH2 gene. The E402K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, it has previously been identified in other unrelated individuals who underwent genetic testing for cardiomyopathy or sudden unexpected death at GeneDx and has been classified as a variant of uncertain significance by another clinical laboratory (Landrum et al., 2014). The E402K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where only amino acids with similar properties to Glutamic acid are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The NHLBI Exome Sequencing Project reports E402K was observed in 8/8,600 alleles from individuals of European background. Furthermore, only one missense variant in a nearby residue (A405S) has been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757413	SCV000885622	uncertain significance	not provided	2017-07-07	criteria provided, single submitter	clinical testing	The p.Glu402Lys variant (rs147407445) has been reported in ClinVar, but not in the medical literature. This variant is listed in the Genome Aggregation Database (gnomAD) Browser with an overall population frequency of 0.03 percent (identified on 81 out of 275,606 chromosomes). The glutamic acid at position 402 is highly conserved from human to sea squirt (Alamut v2.9.0), and computational analyses of the effects of the p.Glu402Lys variant on protein structure and function is conflicting (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: probably damaging). Altogether, there is not enough evidence to classify the p.Glu402Lys variant with certainty.
Fulgent Genetics, Fulgent Genetics	RCV002478520	SCV000895238	uncertain significance	Hypertrophic cardiomyopathy 17; Cardiomyopathy, dilated, 2E	2021-08-02	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845320	SCV000987363	uncertain significance	Primary familial hypertrophic cardiomyopathy		criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000168201	SCV000995240	uncertain significance	Hypertrophic cardiomyopathy	2018-11-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345558	SCV002654145	uncertain significance	Cardiovascular phenotype	2022-11-17	criteria provided, single submitter	clinical testing	The p.E402K variant (also known as c.1204G>A), located in coding exon 3 of the JPH2 gene, results from a G to A substitution at nucleotide position 1204. The glutamic acid at codon 402 is replaced by lysine, an amino acid with similar properties. This variant was observed in a stillbirth case which was tested on a next-generation sequencing panel for cardiac cardiomyopathy and channelopathy genes; however, clinical details were limited (Sahlin E et al. PLoS One, 2019 Jan;14:e0210017). This amino acid position is well conserved in available 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000217886	SCV003928499	likely benign	not specified	2023-04-15	criteria provided, single submitter	clinical testing	Variant summary: JPH2 c.1204G>A (p.Glu402Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 249762 control chromosomes (gnomAD), predominantly at a frequency of 0.00056 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in JPH2 causing Cardiomyopathy (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Seven ClinVar submitters have assessed the variant since 2014: all have classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV000757413	SCV001919598	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000757413	SCV001932210	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000757413	SCV001954696	likely benign	not provided		no assertion criteria provided	clinical testing