Submissions for variant NM_020433.5(JPH2):c.1598G>A (p.Arg533His)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002398560	SCV002707811	uncertain significance	Cardiovascular phenotype	2020-06-22	criteria provided, single submitter	clinical testing	The p.R533H variant (also known as c.1598G>A), located in coding exon 4 of the JPH2 gene, results from a G to A substitution at nucleotide position 1598. The arginine at codon 533 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, histidine 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224632	SCV003920077	uncertain significance	Hypertrophic cardiomyopathy 17; Cardiomyopathy, dilated, 2E	2021-03-30	criteria provided, single submitter	clinical testing	JPH2 NM_020433.4 exon4 p.Arg533His (c.1598G>A): This variant has not been reported in the literature and is not present in large control databases. Evolutionary conservation for this variant is limited or unavailable; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003774399	SCV004688088	uncertain significance	Hypertrophic cardiomyopathy	2023-07-19	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 1776043). This variant has not been reported in the literature in individuals affected with JPH2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 533 of the JPH2 protein (p.Arg533His).