ClinVar Miner

Submissions for variant NM_020433.5(JPH2):c.1720A>G (p.Thr574Ala)

gnomAD frequency: 0.00003  dbSNP: rs773306912
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001772966 SCV002003661 uncertain significance not provided 2021-04-06 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); In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics RCV002405307 SCV002712614 likely benign Cardiovascular phenotype 2024-08-26 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV002540555 SCV003472835 uncertain significance Hypertrophic cardiomyopathy 2024-02-26 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 574 of the JPH2 protein (p.Thr574Ala). This variant is present in population databases (rs773306912, gnomAD 0.008%). 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: 1314457). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004587211 SCV005076988 uncertain significance not specified 2024-04-23 criteria provided, single submitter clinical testing Variant summary: JPH2 c.1720A>G (p.Thr574Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 1570958 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in JPH2 causing Cardiomyopathy (1.7e-05 vs 2.5e-05), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1720A>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1314457). Based on the evidence outlined above, the variant was classified as uncertain significance.

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