Submissions for variant NM_020433.5(JPH2):c.838G>A (p.Glu280Lys)

gnomAD frequency: 0.00001  dbSNP: rs748282723

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493136	SCV000582294	uncertain significance	not specified	2017-05-08	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the JPH2 gene. The E280K variant has notbeen published as pathogenic or been reported as benign to our knowledge. The E280K variant is anon-conservative amino acid substitution, which is likely to impact secondary protein structure asthese residues differ in polarity, charge, size and/or other properties. This substitution occurs at aposition where amino acids with similar properties to glutamic acid (E) are tolerated across species. Insilico analysis predicts this variant is probably damaging to the protein structure/function.Nevertheless, this variant has not been observed in a significant number of affected individuals, and itlacks large segregation studies and functional evidence which would clarify its pathogenicity.Additionally, the E280K variant is observed in 8/12230 (0.06%) alleles from individuals of SouthAsian ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015;Exome Variant Server).
Ambry Genetics	RCV000621828	SCV000740043	likely benign	Cardiovascular phenotype	2020-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Fulgent Genetics, Fulgent Genetics	RCV000764237	SCV000895240	uncertain significance	Hypertrophic cardiomyopathy 17	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000764237	SCV001528092	uncertain significance	Hypertrophic cardiomyopathy 17	2018-04-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae	RCV002527084	SCV003278800	uncertain significance	Hypertrophic cardiomyopathy	2023-08-16	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 280 of the JPH2 protein (p.Glu280Lys). This variant is present in population databases (rs748282723, gnomAD 0.07%), 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: 429669). 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 tolerated. 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000764237	SCV004100547	uncertain significance	Hypertrophic cardiomyopathy 17		criteria provided, single submitter	clinical testing	The missense variant p.E280K in JPH2 (NM_020433.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. It has been submitted to ClinVar as Uncertain Significance.The p.E280K variant is observed in 20/28,876 (0.0693%) alleles from individuals of South Asian background in gnomAD Exomes, which is greater than expected for the disorder. There is a small physicochemical difference between glutamic acid and lysine, which is not likely to impact secondary protein structure as these residues share similar properties. The p.E280K missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.838 in JPH2 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.