rs727503401
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PM5PP2PP3_StrongBS2
The NM_001035.3(RYR2):c.6983C>T(p.Pro2328Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,648 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2328A) has been classified as Pathogenic.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.6983C>T | p.Pro2328Leu | missense_variant | 46/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.6983C>T | p.Pro2328Leu | missense_variant | 46/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.6983C>T | p.Pro2328Leu | missense_variant | 46/106 | ||||
RYR2 | ENST00000659194.3 | c.6983C>T | p.Pro2328Leu | missense_variant | 46/105 | ||||
RYR2 | ENST00000609119.2 | c.6983C>T | p.Pro2328Leu | missense_variant, NMD_transcript_variant | 46/104 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249156Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135180
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461648Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727108
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 20, 2013 | Variant classified as Uncertain Significance - Favor Pathogenic. The Pro2328Leu variant in RYR2 has not been reported in individuals with cardiomyopathy or in l arge population studies. However, another variant at this position, Pro2328Ser, is strongly associated with CPVT, and segregated with disease in >10 individuals in one family (Laitinen 2001, Lehnart 2004), suggesting that a change at this p osition would not be tolerated. In addition, computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest th at the Pro2328Leu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Although this data supports that the Pro2328Leu variant may be pathogenic, additional studies are needed to fully assess its clinical significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 04, 2020 | Variant summary: RYR2 c.6983C>T (p.Pro2328Leu) results in a non-conservative amino acid change located in the RIH Domain (IPR000699) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249156 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6983C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. However, another variant resulting in a different amino acid substitution at the same position (c.6982C>T, p.P2328S) has been reported in the literature in individuals affected with tachycardia (e.g. PMID: 15197150). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 09, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro2328 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15197150; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 165105). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (rs727503401, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2328 of the RYR2 protein (p.Pro2328Leu). - |
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 08, 2023 | This missense variant replaces proline with leucine at codon 2328 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the cytoplasmic domain. Rare nontruncating variants in this region (a.a. 2138-2538) have been shown to be significantly overrepresented in individuals with catecholaminergic polymorphic ventricular tachycardia (PMID: 19926015, 30696458). This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 1/249156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Pro2328Ser (Clinvar variation ID: 12960), is known to cause familial polymorphic ventricular tachycardia, suggesting that proline at this position is important for RYR2 protein function. Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 19, 2023 | This missense variant replaces proline with leucine at codon 2328 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the cytoplasmic domain. Rare nontruncating variants in this region (a.a. 2138-2538) have been shown to be significantly overrepresented in individuals with catecholaminergic polymorphic ventricular tachycardia (PMID: 19926015, 30696458). This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 1/249156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Pro2328Ser (Clinvar variation ID: 12960), is known to cause familial polymorphic ventricular tachycardia, suggesting that proline at this position is important for RYR2 protein function. Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at