chr19-38584992-G-A

Position:

• chr19-38584992-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000540.3(RYR1):​c.14696G>A​(p.Gly4899Glu) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G4899R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 29)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 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 13 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, 8 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 chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR1. . Gene score misZ 1.918 (greater than the threshold 3.09). Trascript score misZ 3.9788 (greater than threshold 3.09). GenCC has associacion of gene with King-Denborough syndrome, congenital multicore myopathy with external ophthalmoplegia, autosomal recessive centronuclear myopathy, RYR1-related myopathy, lethal multiple pterygium syndrome, malignant hyperthermia of anesthesia, benign Samaritan congenital myopathy, malignant hyperthermia, susceptibility to, 1, congenital myopathy with myasthenic-like onset, central core myopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 19-38584992-G-A is Pathogenic according to our data. Variant chr19-38584992-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 65948.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-38584992-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.14696G>A	p.Gly4899Glu	missense_variant	102/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.14696G>A	p.Gly4899Glu	missense_variant	102/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Central core myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

May 11, 2010

- -

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2022

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly4899 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11741831, 12642598, 18171678, 20461000). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RYR1 function (PMID: 12642598, 15175001, 18171678). 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. ClinVar contains an entry for this variant (Variation ID: 65948). This missense change has been observed in individuals with central core disease and autosomal dominant congenital myopathy (PMID: 11709545, 12937085, 16621918). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 4899 of the RYR1 protein (p.Gly4899Glu). -

not provided Other:1

not provided, no classification provided

literature only

Leiden Muscular Dystrophy (RYR1)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.97	.;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	.;M
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.94		.;Gain of solvent accessibility (P = 0.0411);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.89
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs118192183; hg19: chr19-39075632;