Submissions for variant NM_020433.5(JPH2):c.1852A>G (p.Thr618Ala)

gnomAD frequency: 0.00017  dbSNP: rs376612687

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766783	SCV000590375	likely benign	not provided	2021-03-23	criteria provided, single submitter	clinical testing	Has not been previously reported as pathogenic or benign to our knowledge; Reported in ClinVar (ClinVar Variant ID# 432626; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000498785	SCV000711667	likely benign	not specified	2018-06-06	criteria provided, single submitter	clinical testing	p.Thr618Ala in exon 4 of JPH2: This variant is not expected to have clinical si gnificance because it has been identified in 0.04% (51/117444) of European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org; dbSNP rs376612687) and computational prediction tools and conservation anal ysis suggest that the p.Thr618Ala variant may not impact the protein. ACMG/AMP C riteria applied: BS1; BP4.
Ambry Genetics	RCV000619678	SCV000739950	uncertain significance	Cardiovascular phenotype	2022-07-26	criteria provided, single submitter	clinical testing	The p.T618A variant (also known as c.1852A>G), located in coding exon 4 of the JPH2 gene, results from an A to G substitution at nucleotide position 1852. The threonine at codon 618 is replaced by alanine, an amino acid with similar properties. This amino acid position is not 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.
Invitae	RCV000696678	SCV000825251	uncertain significance	Hypertrophic cardiomyopathy	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 618 of the JPH2 protein (p.Thr618Ala). This variant is present in population databases (rs376612687, gnomAD 0.04%), 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: 432626). 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.
Clinical Genetics, Academic Medical Center	RCV000766783	SCV001920885	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000766783	SCV001951461	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766783	SCV001968790	likely benign	not provided		no assertion criteria provided	clinical testing