rs118192151

chr19-38584974-G-Achr19-38584974-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Strong

The NM_000540.3(RYR1):c.14678G>A(p.Arg4893Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4893P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 29)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:8 U:1 O:1
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000540.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-38584974-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2738605.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-38584974-G-A is Pathogenic according to our data. Variant chr19-38584974-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 65988.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Pathogenic=4, not_provided=1, Uncertain_significance=1}. Variant chr19-38584974-G-A is described in Lovd as [Likely_pathogenic]. Variant chr19-38584974-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.14678G>A	p.Arg4893Gln	missense_variant	102/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.14678G>A	p.Arg4893Gln	missense_variant	102/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:8 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 14, 2016	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 11709545, 20301565, 25331388, 12565913, 23183335, 25214167, 15564033, 20681998, 22550088, 35693006, 31130284, 25628744, 16917943, 35081925, 17483490, 33646171, 29669168, 30236257) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2023	- -

RYR1-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 24, 2022	Variant summary: RYR1 c.14678G>A (p.Arg4893Gln) results in a conservative amino acid change located in the Ion transport domain (IPR005821) 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 282656 control chromosomes (gnomAD and publication data). c.14678G>A has been reported in the literature in multiple individuals affected with Central Core Disease and Malignant Hyperthermia Susceptibility (e.g. Davis_2003, Chang_2013, Kraeva_2013, Jung_2015, Miller_2018). In addition, this variant was co-segregated with disease in at least two unrelative families (Chang_2013, Miller_2018). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function showed that equivalent mutations in rabbit RYR1 has equivalent Ca2+ signaling activity as an RYR1 null control in a cell transfection assay (Kraeva_2013) and showed 60% reduction in voltage sensitivity when assayed via electrophysiology (Kraeva_2013). Different missense substitutions at this codon (R4893P, R4893W) were reported in individuals affected with Central core disease in HGMD database (PMID: 16621918, 11709545). This suggests that the arginine residue is critical for RYR1 protein function and that other missense substitutions at this position may also be pathogenic (R4893P and R4893W have been classified as pathogenic in ClinVar database). Six ClinVar submitters, including one expert panel, has assessed the variant since 2014: the variant was classified as of uncertain significance by the expert panel, as likely pathogenic by one laboratory, and pathogenic by four laboratories. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 4893 of the RYR1 protein (p.Arg4893Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant malignant hyperthermia and central core disease (CCD) (PMID: 12565913, 22550088, 23183335, 25628744, 30236257). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65988). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects RYR1 function (PMID: 23183335). This variant disrupts the p.Arg4893 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11709545, 14670767). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2023

The c.14678G>A (p.R4893Q) alteration is located in exon 102 (coding exon 102) of the RYR1 gene. This alteration results from a G to A substitution at nucleotide position 14678, causing the arginine (R) at amino acid position 4893 to be replaced by a glutamine (Q)._x000D_ _x000D_ for autosomal dominant RYR1-related myopathy; however, its clinical significance for autosomal dominant malignant hyperthermia susceptibility is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in the heterozygous state in multiple individuals with central core disease or other clinical symptoms of RYR1-related myopathy (Zhou, 2007; Kraeva, 2013; Savarese, 2014; Jung, 2015; Todd, 2018; Monies, 2019; Chang, 2022). It has been observed to segregate with disease in one family with central core disease (Chang, 2013). Additionally, this variant has also been observed in three unrelated families with malignant hyperthermia susceptibility (Miller, 2018). Another alteration at the same codon, c.14677C>T (p.R4893W), has been reported in individuals with clinical features consistent with RYR1-related myopathy (Monnier, 2001; Quinlivan, 2003). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Central core myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

May 11, 2010

- -

Malignant hyperthermia of anesthesia Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Apr 07, 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 arginine with glutamine at codon 4893 of the RYR1 protein, p.(Arg4893Gln). This variant was not present in a large population database (gnomAD) at the time this variant was interpreted. To our knowledge this variant has not been reported in the literature in individuals who have a personal or family history of a malignant hyperthermia reaction (PMID:30236257, UK (Leeds) MH Investigational Unit). No functional studies were identified for this variant. This variant resides in a region of RYR1 considered to be a hotspot for pathogenic variants that contribute to MHS, PM1_Supporting (PMID: 21118704). A REVEL score >0.85 (0.963) supports a pathogenic status for this variant, PP3_Moderate. This variant has been classified as a Variant of Uncertain Significance. Criteria implemented: PM1_Supporting, PP3_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	34
Dann	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.87		.;Loss of methylation at R4893 (P = 0.0194);
MVP		1.0
MPC		0.78
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.94
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.58		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: rs118192151; hg19: chr19-39075614; COSMIC: COSV100614374; COSMIC: COSV100614374;