rs767777113
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_000540.3(RYR1):c.328C>T(p.His110Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,018 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. H110Q) has been classified 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 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.328C>T | p.His110Tyr | missense_variant | 4/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.328C>T | p.His110Tyr | missense_variant | 4/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.328C>T | p.His110Tyr | missense_variant | 4/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.328C>T | p.His110Tyr | missense_variant, NMD_transcript_variant | 4/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251278Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135820
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461844Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727226
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74344
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 13, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In addition, in silico splice predictors suggests this variant may lead to abnormal gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 29261186, 30652412) - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 09, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 23, 2023 | Variant summary: RYR1 c.328C>T (p.His110Tyr) results in a conservative amino acid change to a highly conserved residue (HGMD) located in the Inositol 1,4,5-trisphosphate/ryanodine receptor (IPR014821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251278 control chromosomes (gnomAD). c.328C>T has been reported in the literature in an individual affected with Malignant Hyperthermia Susceptibility (Endo_2022) and in a foetal akinesia case where the variant was found in trans with another variant of uncertain significance (Boissel_2018, Alkhunaizi_2019). 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 publications have been ascertained in the context of this evaluation (PMID: 29261186, 30652412, 35697689). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. 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