Submissions for variant NM_020433.5(JPH2):c.1564C>T (p.Arg522Trp)

gnomAD frequency: 0.00002  dbSNP: rs770850932

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208107	SCV000263960	uncertain significance	Primary dilated cardiomyopathy	2015-09-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001219739	SCV001391692	uncertain significance	Hypertrophic cardiomyopathy	2023-05-23	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 disruptive. ClinVar contains an entry for this variant (Variation ID: 222659). This variant has not been reported in the literature in individuals affected with JPH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 522 of the JPH2 protein (p.Arg522Trp).
Ambry Genetics	RCV002399769	SCV002707722	uncertain significance	Cardiovascular phenotype	2024-02-01	criteria provided, single submitter	clinical testing	The p.R522W variant (also known as c.1564C>T), located in coding exon 4 of the JPH2 gene, results from a C to T substitution at nucleotide position 1564. The arginine at codon 522 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was reported in a Swedish stillbirth cohort (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.
GeneDx	RCV001529733	SCV005421853	uncertain significance	not provided	2024-06-03	criteria provided, single submitter	clinical testing	Identified in a stillbirth case without chromosomal abnormalities and in a patient with polycystic kidney disease and heart failure who harbored a pathogenic variant in PKD1 and was compound heterozygous for two JPH2 variants as well as other cardiogenetic variants (PMID: 30615648, 32879264); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30615648, 30235249, 32879264)
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529733	SCV001743699	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001529733	SCV001920859	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529733	SCV001956673	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001529733	SCV001978422	uncertain significance	not provided		no assertion criteria provided	clinical testing