19-38452916-A-T
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP2PP3_ModeratePP5_Very_Strong
The NM_000540.3(RYR1):c.1342A>T(p.Ile448Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,512 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I448I) has been classified as Likely benign.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.1342A>T | p.Ile448Phe | missense_variant | 13/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.1342A>T | p.Ile448Phe | missense_variant | 13/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.1342A>T | p.Ile448Phe | missense_variant | 13/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.1342A>T | p.Ile448Phe | missense_variant, NMD_transcript_variant | 13/80 | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249700Hom.: 0 AF XY: 0.00000739 AC XY: 1AN XY: 135302
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461512Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727084
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
RYR1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 448 of the RYR1 protein (p.Ile448Phe). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 28269792, 28818389). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 571022). 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. For these reasons, this variant has been classified as Pathogenic. - |
Centronuclear myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire | Mar 01, 2024 | PM2+PM3+PP2+PP3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at