chr1-237042558-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_ModeratePM2PP2PP3PP5
The NM_001035.3(RYR2):āc.37T>Cā(p.Phe13Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F13C) 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_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR2 | NM_001035.3 | c.37T>C | p.Phe13Leu | missense_variant | 1/105 | ENST00000366574.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR2 | ENST00000366574.7 | c.37T>C | p.Phe13Leu | missense_variant | 1/105 | 1 | NM_001035.3 | P1 | |
RYR2 | ENST00000660292.2 | c.37T>C | p.Phe13Leu | missense_variant | 1/106 | ||||
RYR2 | ENST00000659194.3 | c.37T>C | p.Phe13Leu | missense_variant | 1/105 | ||||
RYR2 | ENST00000609119.2 | c.37T>C | p.Phe13Leu | missense_variant, NMD_transcript_variant | 1/104 | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1109596Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 525684
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 17, 2020 | Variant summary: RYR2 c.37T>C (p.Phe13Leu) results in a non-conservative amino acid change located in the Inositol 1,4,5-trisphosphate/ryanodine receptor domain (IPR014821) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 39990 control chromosomes (gnomAD). c.37T>C has been reported in the literature in five individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia from one family, and authors classified the variant as likely pathogenic based on phenotype-enhanced ACMG variant classification framework (Giudicessi_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 08, 2022 | 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 expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 201289). This missense change has been observed in individuals with RYR2-related conditions (PMID: 31112425; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 13 of the RYR2 protein (p.Phe13Leu). For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 26, 2023 | The c.37T>C (p.F13L) alteration is located in exon 1 (coding exon 1) of the RYR2 gene. This alteration results from a T to C substitution at nucleotide position 37, causing the phenylalanine (F) at amino acid position 13 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at