19-38458056-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate
The NM_000540.3(RYR1):c.1931G>T(p.Arg644Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,296 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 Uncertain significance (★).
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.1931G>T | p.Arg644Leu | missense_variant | Exon 18 of 106 | 5 | NM_000540.3 | ENSP00000352608.2 | ||
RYR1 | ENST00000355481.8 | c.1931G>T | p.Arg644Leu | missense_variant | Exon 18 of 105 | 1 | ENSP00000347667.3 | |||
RYR1 | ENST00000599547.6 | n.1931G>T | non_coding_transcript_exon_variant | Exon 18 of 80 | 2 | ENSP00000471601.2 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461296Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726898
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: RYR1 c.1931G>T (p.Arg644Leu) results in a non-conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250488 control chromosomes. c.1931G>T has been reported in the literature in individuals affected with Myopathy (Klein_2012). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 22473935). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.