rs193922877

chr19-38580126-CA-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 10P and 8B. PVS1 PM2 BP6_Very_Strong

The NM_000540.3(RYR1):c.14510del(p.Gln4837ArgfsTer3) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RYR1 NM_000540.3 frameshift, splice_region
• Clinical Significance: Likely benign reviewed by expert panel B:1 O:1
• Conservation: PhyloP100: 9.31

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 19-38580126-CA-C is Benign according to our data. Variant chr19-38580126-CA-C is described in ClinVar as [Likely_benign]. Clinvar id is 133073.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-38580126-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.14510del	p.Gln4837ArgfsTer3	frameshift_variant, splice_region_variant	100/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.14510del	p.Gln4837ArgfsTer3	frameshift_variant, splice_region_variant	100/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Malignant hyperthermia of anesthesia Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Mar 14, 2022

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 frameshift variant, p.Gln4837Argfs*3, predicts the substitution of glutamine with arginine at codon 4837 and a premature stop codon at position 3 of the new reading frame. This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. This variant has been reported in an individual with a personal or family history of an MH episode and a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted), PS4_Supporting (PMID:17293538). Two relatives of this individual were shown to be heterozygous for the variant and IVCT negative, BS2_Moderate was implemented. This variant predicts a loss of function due to nonsense mediated decay, loss of function variants are not expected to cause MH. Experiments expressing this variant in HEK293 cells did not demonstrate NMD as determined by protein expression on a Western blot. Expression of this variant alone showed no calcium release upon stimulation with caffeine, when the variant was transfected with wild-type RYR1 the EC50 was comparable to that observed in cells expressing wild-type RYR1 alone, BS3_Supporting was applied (PMID:17293538). Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386), (relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern). Criteria implemented: PS4_Supporting, BS2_Moderate, BS3_Supporting. -

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

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- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.38		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193922877; hg19: chr19-39070766;