1-237566672-C-T
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2
The NM_001035.3(RYR2):c.3320C>T(p.Thr1107Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,613,804 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. T1107T) has been classified as Likely benign.
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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.3320C>T | p.Thr1107Met | missense_variant | 28/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.3320C>T | p.Thr1107Met | missense_variant | 28/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.3320C>T | p.Thr1107Met | missense_variant | 28/106 | ||||
RYR2 | ENST00000659194.3 | c.3320C>T | p.Thr1107Met | missense_variant | 28/105 | ||||
RYR2 | ENST00000609119.2 | c.3320C>T | p.Thr1107Met | missense_variant, NMD_transcript_variant | 28/104 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000526 AC: 80AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000421 AC: 105AN: 249172Hom.: 0 AF XY: 0.000436 AC XY: 59AN XY: 135178
GnomAD4 exome AF: 0.000815 AC: 1192AN: 1461686Hom.: 1 Cov.: 31 AF XY: 0.000773 AC XY: 562AN XY: 727130
GnomAD4 genome AF: 0.000526 AC: 80AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38AN XY: 74310
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:4
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 16, 2020 | This variant is associated with the following publications: (PMID: 23861362, 27538377, 27435932, 22374134, 19926015, 24025405, 20157052, 22677073, 26573135, 25370123, 28404607, 28567303, 30403697, 29396286) - |
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Feb 02, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | RYR2: BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 07, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 21, 2022 | - - |
not specified Uncertain:1Benign: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.Thr1107Met variant in RYR2 has been reported in an individual with CVPT, a case of SIDS, a Japanese family with HCM, an individual with DCM, and as a secondary finding in an individual with oculocutaneous albinism without mention of cardiac phenotype (Medeiros-Domingo et al 2009, Methner et al. 2016, Stavropolous et al. 2017, Noboru et al. 2006 (abstract only), LMM data). It has been reported in ClinVar (Variation ID #43768). In vitro functional studies provide some evidence that the p.Thr1107Met variant may impact protein function (Tang et al. 2012). However, these types of assays may not accurately represent biological function. This variant has been identified in 79/126600 of European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs200236750). Threonine (Thr) at position 1107 is not conserved in mammals or evolutionarily distant species, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, due to conflicting data, the clinical significance of the p.Thr1107Met variant is uncertain. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 07, 2021 | Variant summary: RYR2 c.3320C>T (p.Thr1107Met) results in a non-conservative amino acid change located in the Ryanodine receptor, SPRY domain 2 & B30.2/SPRY domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 249172 control chromosomes, predominantly at a frequency of 0.00085 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 14 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 South Asian origin. c.3320C>T has been reported in the literature in individuals affected with Arrhythmia and other cardiopathologies (example: Fujino_2006, Tester_2012, Medeiros-Domingo_2009, Ghazani_2017, Landstrom_2017, Methner_2016, Rangaraju_2018, Roston_2018, Stavropoulos_2016). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrences with other pathogenic variants have been reported (KCNH2 c.2398+5G>T; CASQ2 IVS5+1G>C (c.606+1G>C); MYH7 c.1447G>A/p.E483K) (Roston_2018, Tester_2012, Internal database), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (example: Tang_2012). The most pronounced variant effect results in >50%-90% of normal activity. Seven ClinVar submitters have assessed this variant since 2014: three report the variant as likely benign, three as of uncertain significance, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Death in infancy Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences | Mar 27, 2015 | - - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 05, 2019 | - - |
RYR2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 10, 2023 | 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
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 10, 2021 | 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