rs201500134
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2
The NM_001035.3(RYR2):āc.8162T>Cā(p.Ile2721Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,519,710 control chromosomes in the GnomAD database, including 6 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. I2721L) has been classified as Uncertain significance.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RYR2 | ENST00000366574.7 | c.8162T>C | p.Ile2721Thr | missense_variant | Exon 54 of 105 | 1 | NM_001035.3 | ENSP00000355533.2 | ||
| RYR2 | ENST00000609119.2 | n.8162T>C | non_coding_transcript_exon_variant | Exon 54 of 104 | 5 | ENSP00000499659.2 | ||||
| RYR2 | ENST00000660292.2 | c.8162T>C | p.Ile2721Thr | missense_variant | Exon 54 of 106 | ENSP00000499787.2 | ||||
| RYR2 | ENST00000659194.3 | c.8162T>C | p.Ile2721Thr | missense_variant | Exon 54 of 105 | ENSP00000499653.3 |
Frequencies
GnomAD3 genomes 0.000644 AC: 98AN: 152064Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000575 AC: 79AN: 137332Hom.: 0 AF XY: 0.000577 AC XY: 42AN XY: 72842
GnomAD4 exome AF: 0.00138 AC: 1881AN: 1367528Hom.: 6 Cov.: 26 AF XY: 0.00137 AC XY: 922AN XY: 674114
GnomAD4 genome 0.000644 AC: 98AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39AN XY: 74400
ClinVar
Submissions by phenotype
not provided Benign:5
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not specified Uncertain:3Benign:1
The Ile2721Thr variant in RYR2 has not been reported in the literature nor previ ously identified by our laboratory. This variant has been identified in 4/7968 E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS). Computational analyses (biochemic al amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not p rovide strong support for or against an impact to the protein. Additional inform ation is needed to fully assess the clinical significance of this variant. -
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The I2721T variant of uncertain significance in the RYR2 gene has been previously reported intwo individuals (van Spaendonck-Zwarts et al., 2014; Hertz et al., 2015). This variant was initiallyreported as a variant of uncertain significance in one individual with atrial fibrillation and dilatedcardiomyopathy who was found to harbor additional variants of uncertain significance in theDMD and TTN genes (van Spaendonck-Zwarts et al., 2014). Subsequently, Hertz et al. (2015)reported I2721T in an individual diagnosed with Long QT syndrome at 19 years of age; however,she was also found to harbor a KCNH2 variant classified as likely pathogenic. This variant hasalso been identified independently and in conjunction with additional cardiogenetic variants inindividuals referred for arrhythmia and cardiomyopathy genetic testing at GeneDx; however, thusfar, segregation data is limited or absent for these individuals due to the lack of clinical informationprovided and/or insufficient participation by informative family members. Additionally, theI2721T variant is classified in ClinVar as a variant of uncertain significance by two clinicallaboratories (ClinVar SCV000060449.4; SCV000285751.1; Landrum et al., 2016). The I2721Tvariant was not observed with any significant frequency in approximately 5,800 individuals ofEuropean and African American ancestry in the NHLBI Exome Sequencing Project. Although thissubstitution occurs at a position where amino acids with similar properties to Isoleucine aretolerated across species, the I2721T variant is a non-conservative amino acid substitution, which islikely to impact secondary protein structure as these residues differ in polarity, charge, size and/orother properties. Consequently, in silico analysis predicts this variant is probably damaging to theprotein structure/function. Nevertheless, the I2721T variant is not located in one of the threehot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur(Medeiros-Domingo et al., 2009).Therefore, based on the currently available information, it is unclear whether this variant ispathogenic or rare benign. -
Variant summary: RYR2 c.8162T>C (p.Ile2721Thr) results in a non-conservative amino acid change located in the Ryanodine receptor Ryr domain (IPR003032) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 137452 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.8162T>C has been reported in the literature in individuals affected with Arrhythmia, LQTS, catecholaminergic polymorphic ventricular tachycardia, sudden arrhythmic death syndrome and Wolff-Parkinson-White syndrome (vanSpaendonck_2014, Hertz_2014, Landstrom_2017, Munroe_2018, Raju_2019, Coban-Akdemir_2020). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrences with other pathogenic variants have been reported (TTN c.86171_86174dupAAAG, p.Asn28726Lysfs*3; LMNA c.725C>T, p.Ala242Val; KCNH2 c.1286del, p.A429Vfs*5), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (6x) and likely benign (5x). Based on the evidence outlined above, the variant was classified as likely benign. -
Cardiomyopathy Benign:2
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Likely Benign variant based on current evidence: This missense variant is located in the cytoplasmic domain of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with long QT syndrome, who also carried a pathogenic truncation variant in the KCNH2 gene (PMID: 25467552). This variant has been identified in 97/163874 chromosomes (84/68536 non-Finnish European chromosomes, 0.1225%) in the general population by the Genome Aggregation Database (gnomAD). This variant allele frequency is greater than expected for the RYR2-related disorder based on prevalence, penetrance, and genetic heterogeneity. Based on available evidence, this variant is classified as Likely Benign. -
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2
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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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Wolff-Parkinson-White pattern Uncertain:1
This variant was identified in an individual with Wolff-Parkinson-White syndrome -
Arrhythmogenic right ventricular cardiomyopathy Uncertain:1
Found in patient having exome sequencing for an unrelated indication. No known history of arrhythmogenic right ventricular dysplasia. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -
Arrhythmogenic right ventricular dysplasia 2 Uncertain:1
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. -
Catecholaminergic polymorphic ventricular tachycardia Benign:1
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RYR2-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Cardiovascular phenotype Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at