19-38580033-A-G
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP2PP3_ModeratePP5
The NM_000540.3(RYR1):āc.14416A>Gā(p.Asn4806Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. N4806K) has been classified as Uncertain significance.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.14416A>G | p.Asn4806Asp | missense_variant | 100/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.14416A>G | p.Asn4806Asp | missense_variant | 100/106 | 5 | NM_000540.3 | A2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461888Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727246
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Pathogenic:3Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 19, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2019 | Published functional studies demonstrate an impairment of the calcium release channel function and regulation at the Asn4806 residue (Du et al., 1998); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22473935, 28818389, 27234031, 9822655) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | May 16, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 07, 2015 | - - |
RYR1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 30, 2022 | This missense change has been observed in individuals with autosomal recessive RYR1-related conditions (PMID: 22473935, 25960145, 27234031, 28818389). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 4806 of the RYR1 protein (p.Asn4806Asp). ClinVar contains an entry for this variant (Variation ID: 265505). For these reasons, this variant has been classified as Pathogenic. 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 RYR1 protein function. - |
RYR1-related myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine | Jan 16, 2023 | - - |
Abnormality of the musculature Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Jan 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at