rs1258920337
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_020433.5(JPH2):c.590G>T(p.Arg197Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000799 in 1,251,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R197C) has been classified as Uncertain significance.
Frequency
Consequence
NM_020433.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
JPH2 | NM_020433.5 | c.590G>T | p.Arg197Leu | missense_variant | 2/6 | ENST00000372980.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
JPH2 | ENST00000372980.4 | c.590G>T | p.Arg197Leu | missense_variant | 2/6 | 5 | NM_020433.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 151768Hom.: 0 Cov.: 32 FAILED QC
GnomAD4 exome AF: 0.00000799 AC: 10AN: 1251218Hom.: 0 Cov.: 32 AF XY: 0.00000491 AC XY: 3AN XY: 610822
GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 151768Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74138
ClinVar
Submissions by phenotype
Hypertrophic cardiomyopathy 17;C5561970:Cardiomyopathy, dilated, 2E Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 07, 2021 | - - |
Hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 10, 2023 | This variant has not been reported in the literature in individuals affected with JPH2-related conditions. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 524960). 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 leucine, which is neutral and non-polar, at codon 197 of the JPH2 protein (p.Arg197Leu). - |
Cardiomyopathy, dilated, 2E Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genomics Laboratory, Stanford Medicine | Jun 11, 2021 | The p.Arg197Leu variant in the JPH2 gene has not been previously reported in association with disease. This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/); however, this region is indicated to have poor coverage. Computational tools predict that the p.Arg197Leu variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Arg197Leu variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2_Supporting, PP3] - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2021 | The p.R197L variant (also known as c.590G>T), located in coding exon 2 of the JPH2 gene, results from a G to T substitution at nucleotide position 590. The arginine at codon 197 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in a hypertrophic cardiomyopathy (HCM) cohort (Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at