rs140616359
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
This summary comes from the ClinGen Evidence Repository: This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions.This sequence variant predicts a substitution of valine with isoleucine at codon 3840 of the RYR1 protein, p.(Val3840Ile). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00040, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without an in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16732084). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.648 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. LINK:https://erepo.genome.network/evrepo/ui/classification/CA023914/MONDO:0007783/012
Frequency
Consequence
NM_000540.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.11518G>A | p.Val3840Ile | missense_variant, splice_region_variant | 82/106 | ENST00000359596.8 | |
LOC124904710 | XR_007067250.1 | n.120-64C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.11518G>A | p.Val3840Ile | missense_variant, splice_region_variant | 82/106 | 5 | NM_000540.3 | A2 | |
ENST00000595853.2 | n.149-64C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152082Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000839 AC: 21AN: 250338Hom.: 0 AF XY: 0.0000813 AC XY: 11AN XY: 135288
GnomAD4 exome AF: 0.0000397 AC: 58AN: 1461464Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30AN XY: 726964
GnomAD4 genome ? AF: 0.0000723 AC: 11AN: 152200Hom.: 0 Cov.: 31 AF XY: 0.0000538 AC XY: 4AN XY: 74416
ClinVar
Submissions by phenotype
Malignant hyperthermia, susceptibility to, 1 Uncertain:2Benign:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen | Apr 06, 2023 | This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of valine with isoleucine at codon 3840 of the RYR1 protein, p.(Val3840Ile). The maximum allele frequency for this variant among the six major gnomAD populations is EAS: 0.00040, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode without an in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (PMID:16732084). No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of 0.648 supports neither a pathogenic nor a benign status for this variant. This variant has been classified as a Variant of Unknown Significance. No criteria implemented. - |
Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jun 02, 2023 | - - |
not provided Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 03, 2021 | In silico analysis supports that this missense variant does not alter protein structure/function; Reported previously in the heterozygous state in an individual with malignant hyperthermia; however parental studies were not performed (Ibarra et al., 2006); This variant is associated with the following publications: (PMID: 16732084, 16917943, 25637381) - |
not provided, no classification provided | literature only | Leiden Muscular Dystrophy (RYR1) | - | - - |
RYR1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 02, 2022 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 3840 of the RYR1 protein (p.Val3840Ile). This variant is present in population databases (rs140616359, gnomAD 0.03%). This missense change has been observed in individual(s) with a family history of malignant hyperthermia and malignant hyperthermia (PMID: 16732084, 16917943). ClinVar contains an entry for this variant (Variation ID: 133013). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at