1-237705281-C-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_001035.3(RYR2):c.9518C>T(p.Thr3173Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,604,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T3173T) has been classified as Benign.
Frequency
Consequence
NM_001035.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.9518C>T | p.Thr3173Ile | missense_variant | 67/105 | ENST00000366574.7 | NP_001026.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.9518C>T | p.Thr3173Ile | missense_variant | 67/105 | 1 | NM_001035.3 | ENSP00000355533 | P1 | |
RYR2 | ENST00000660292.2 | c.9518C>T | p.Thr3173Ile | missense_variant | 67/106 | ENSP00000499787 | ||||
RYR2 | ENST00000659194.3 | c.9518C>T | p.Thr3173Ile | missense_variant | 67/105 | ENSP00000499653 | ||||
RYR2 | ENST00000609119.2 | c.*553C>T | 3_prime_UTR_variant, NMD_transcript_variant | 65/104 | 5 | ENSP00000499659 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000171 AC: 4AN: 234528Hom.: 0 AF XY: 0.0000158 AC XY: 2AN XY: 126618
GnomAD4 exome AF: 0.00000757 AC: 11AN: 1452718Hom.: 0 Cov.: 29 AF XY: 0.00000693 AC XY: 5AN XY: 721660
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152152Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74338
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 10, 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 10/265914 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 28, 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 10/265914 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 03, 2023 | Identified in a cohort of individuals referred for whole exome sequencing; however, specific clinical information about the individual harboring this variant was not provided (Landstrom et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); This variant is associated with the following publications: (PMID: 28404607) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 03, 2023 | The p.T3173I variant (also known as c.9518C>T), located in coding exon 67 of the RYR2 gene, results from a C to T substitution at nucleotide position 9518. The threonine at codon 3173 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at