Submissions for variant NM_020433.5(JPH2):c.1658C>T (p.Ala553Val)

gnomAD frequency: 0.00004  dbSNP: rs200422043

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466072	SCV000541241	uncertain significance	Hypertrophic cardiomyopathy	2024-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 553 of the JPH2 protein (p.Ala553Val). 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 variant has not been reported in the literature in individuals affected with JPH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 403849). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
GeneDx	RCV001577972	SCV001805477	uncertain significance	not provided	2021-04-30	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #403849; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics	RCV002393074	SCV002703245	likely benign	Cardiovascular phenotype	2024-05-15	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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787705	SCV005398743	uncertain significance	Hypertrophic cardiomyopathy 17	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dilated cardiomyopathy 2E (MIM#619492) and hypertrophic cardiomyopathy 17 (MIM#613873). However, the gene-disease associations have not been established conclusively (PanelApp Australia) and were classified as moderate by ClinGen. (I) 0108 - This gene is associated with both recessive and dominant disease. Autosomal recessive and dominant inheritance has been reported for dilated cardiomyopathy 2E (MIM#619492), with biallelic nonsense variants reported in severe, paediatric-onset DCM (PMIDs: 27471098, 30384889, 31227780; OMIM). Hypertrophic cardiomyopathy 17 (MIM#613873) has been associated with autosomal dominant inheritance (OMIM). However, the gene-disease associations have not been established conclusively (PanelApp Australia) and were classified as moderate by ClinGen. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3: 11 heterozygotes, 0 homozygotes). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS by two clinical testing laboratories (ClinVar). It has also been reported once as likely benign however no further information is available (LOVD). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign