chr1-237590901-G-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_001035.3(RYR2):āc.4069G>Cā(p.Asp1357His) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,613,684 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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. D1357N) has been classified as Uncertain significance.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.4069G>C | p.Asp1357His | missense_variant | 31/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.4069G>C | p.Asp1357His | missense_variant | 31/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.4069G>C | p.Asp1357His | missense_variant | 31/106 | ||||
RYR2 | ENST00000659194.3 | c.4069G>C | p.Asp1357His | missense_variant | 31/105 | ||||
RYR2 | ENST00000609119.2 | c.4069G>C | p.Asp1357His | missense_variant, NMD_transcript_variant | 31/104 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000658 AC: 10AN: 152040Hom.: 1 Cov.: 31
GnomAD3 exomes AF: 0.0000483 AC: 12AN: 248560Hom.: 0 AF XY: 0.0000593 AC XY: 8AN XY: 134880
GnomAD4 exome AF: 0.000115 AC: 168AN: 1461644Hom.: 0 Cov.: 31 AF XY: 0.000106 AC XY: 77AN XY: 727106
GnomAD4 genome AF: 0.0000658 AC: 10AN: 152040Hom.: 1 Cov.: 31 AF XY: 0.0000808 AC XY: 6AN XY: 74264
ClinVar
Submissions by phenotype
Cardiomyopathy Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 10, 2023 | This variant is located in the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 15/279946 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 1357 of the RYR2 protein (p.Asp1357His). This variant is present in population databases (rs193922626, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 28807990). ClinVar contains an entry for this variant (Variation ID: 36743). 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 not expected to disrupt RYR2 protein function with a negative predictive value of 95%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 25, 2019 | Variant classified as Uncertain Significance - Favor Benign. The p.Asp1357His variant in RYR2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/8254 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs193922626). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clinical significance of the Asp1357His variant. - |
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | This variant is located in the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 15/279946 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 08, 2022 | The c.4069G>C (p.D1357H) alteration is located in exon 31 (coding exon 31) of the RYR2 gene. This alteration results from a G to C substitution at nucleotide position 4069, causing the aspartic acid (D) at amino acid position 1357 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Arrhythmogenic right ventricular dysplasia 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at