rs371147744
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2
The NM_001035.3(RYR2):c.9655G>A(p.Val3219Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,613,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V3219V) has been classified as Likely benign.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.9655G>A | p.Val3219Met | missense_variant | 68/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.9655G>A | p.Val3219Met | missense_variant | 68/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.9655G>A | p.Val3219Met | missense_variant | 68/106 | ||||
RYR2 | ENST00000659194.3 | c.9655G>A | p.Val3219Met | missense_variant | 68/105 | ||||
RYR2 | ENST00000609119.2 | c.*690G>A | 3_prime_UTR_variant, NMD_transcript_variant | 66/104 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000986 AC: 15AN: 152088Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000763 AC: 19AN: 249136Hom.: 0 AF XY: 0.0000740 AC XY: 10AN XY: 135154
GnomAD4 exome AF: 0.000198 AC: 290AN: 1461630Hom.: 0 Cov.: 31 AF XY: 0.000223 AC XY: 162AN XY: 727102
GnomAD4 genome ? AF: 0.0000986 AC: 15AN: 152088Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6AN XY: 74282
ClinVar
Submissions by phenotype
not specified Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 18, 2023 | Variant summary: RYR2 c.9655G>A (p.Val3219Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 249136 control chromosomes (gnomAD). The observed variant frequency is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.9655G>A has been reported in the literature in individuals affected with presyncope and myocarditis (example: Roux-Buisson_2014 and Seidel_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=7) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 03, 2015 | The p.Val3219Met variant in RYR2 has been reported in 1 individual with ARVC (Ro ux-Buisson 2014) and in 5/66632 European chromosomes by the Exome Aggregation Co nsortium (ExAC, http://exac.broadinstitute.org; dbSNP rrs371147744). Computatio nal prediction tools and conservation analysis suggest that the p.Val3219Met var iant may not impact the protein, though this information is not predictive enoug h to rule out pathogenicity. In summary, the clinical significance of the p.Val3 219Met variant is uncertain. - |
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Mar 31, 2011 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val3219Met (V3219M; c.9655 G>A) in the RYR2 gene: Based on the limited data currently available about this variant (reviewed in detail below), we agree and consider this a variant of unknown significance. This variant has been reported just once in the literature, according to our search, by Roux-Buisson et al. (online publication before print, July 2014). No segregation data is available. They found this variant in one Caucasian male proband recruited in France or Switzerland who was borderline for ARVC by 2010 criteria and who had previously tested negative for variants in desmosomal genes associated with ARVC (PKP2, DSG2, DSP, JUP, and DSC2). This was a sporadic case, with no family history of ARVC, who presented with presyncope at the age of 41. Resting EKG showed T wave inversion from lead V1 to lead V3. 24-hour Holter monitoring detected frequent monomorphic ventricular ectopies decreasing during exercise. Cardiac imaging showed wall motion abnormalities with dyskinesia and RV aneurysm but no RV dilatation and therefore did not reach the 2010 diagnostic criteria. This is a conservative amino acid substitution from a nonpolar valine to a nonpolar methionine at a residue that is not conserved across vertebrate species (Ambry lists at least 7 species it differs in including rat and mouse). This valine is not conserved across paralog proteins (RYR1-RYR3; http://cardiodb.org/Paralogue_Annotation/), and nor are several amino acids nearby. In silico analysis with PolyPhen-2 predicts this variant to be “Possibly Damaging” with a score of 0.631. SIFT predicts that it is tolerated, according to Ambry. Yano et al. (2006) reported that disease-causing variants in RYR2 cluster within 3 hot-spot regions: the N-terminal domain (residues 77-433), the central domain (residues 2246-2534), and the C-terminal domain (residues 3778-4959). This variant does not fall within a known disease-causing hotspot. There are no missense variants at nearby residues (+/-10) listed in HGMD in association with CPVT or ARVC (as of January 2014). This variant is listed in dbSNP as rs371147744. It was submitted twice: Once by the NHLBI ESP, and once by a genome sequencing project in the Netherlands. The variant has been seen in 1 out of ~6,200 individuals from controls and individuals from publicly available population datasets. Of note, none of these match the ethnicity of our patients, which is Filipino. It is present in one Caucasian from the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~4100 Caucasian and ~1900 African American individuals. The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. Roux-Buisson et al. (2014) did not find it in 200 Caucasian controls. There is no variation at this codon listed in 1000 Genomes (as of November 10, 2014). - |
Cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 06, 2023 | This variant is located in the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 21/280528 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Aug 24, 2017 | - - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | RYR2: BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 06, 2016 | A variant of uncertain significance has been identified in the RYR2 gene. The V3219M variant has previously been reported in a 41 year-old patient who had clinical features consistent with ARVC, but did not meet 2010 Task Force Criteria for a diagnosis of ARVC (Roux-Buisson et al., 2014). This variant has also been observed in other unrelated individuals referred for cardiac genetic testing at GeneDx, and has been classified in ClinVar as a variant of uncertain significance by other clinical laboratories (ClinVar SCV000263004.2, SCV000272400.1, SCV000280458.1; Landrum et al., 2016). The V3219M variant was not observed at a significant frequency in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, the V3219M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species, and Methionine is the wild-type amino acid at this position in at least two species. This variant is not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). Furthermore, 2/3 in silico splice prediction programs predict this variant likely does not alter the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This variant is located in the RYR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 21/280528 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. - |
Arrhythmogenic right ventricular dysplasia 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 05, 2024 | The p.V3219M variant (also known as c.9655G>A), located in coding exon 68 of the RYR2 gene, results from a G to A substitution at nucleotide position 9655. The valine at codon 3219 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in a cohort of subjects referred for arrhythmogenic right ventricular cardiomyopathy (ARVC) genetic testing (Roux-Buisson N et al. Heart Rhythm, 2014 Nov;11:1999-2009). This alteration has also been reported in an exome cohort, but cardiovascular history was not provided (Landstrom AP et al. Circ Arrhythm Electrophysiol, 2017 Apr;10). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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