rs118192134

Positions:

• chr19-38572182-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000540.3(RYR1):​c.13910C>T​(p.Thr4637Ile) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T4637A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.76

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]

RYR1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM1: In a topological_domain Lumenal (size 60) in uniprot entity RYR1_HUMAN there are 11 pathogenic changes around while only 1 benign (92%) 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 chr19-38572181-A-G is described in Lovd as [Pathogenic].
• 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, 0.936
• PP5: Variant 19-38572182-C-T is Pathogenic according to our data. Variant chr19-38572182-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 65995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38572182-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.13910C>T	p.Thr4637Ile	missense_variant	95/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.13910C>T	p.Thr4637Ile	missense_variant	95/106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Central core myopathy Pathogenic:2

Pathogenic, no assertion criteria provided	curation	GeneReviews	May 11, 2010	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	May 02, 2023	PS2, PM1, PM2, PM5, PP3, PP5 -

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2019

This sequence change replaces threonine with isoleucine at codon 4637 of the RYR1 protein (p.Thr4637Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. A different missense substitution at this codon (p.Thr4637Ala) has been determined to be pathogenic (PMID: 11113224). This suggests that the threonine residue is critical for RYR1 protein function and that other missense substitutions at this position may also be pathogenic. In addition, this sequence change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has been reported in individuals affected with central core disease and myopathy and has been observed to segregate with disease in a family (PMID: 12565913, Invitae). In addition, this variant was observed de novo in at least one individual (Invitae). ClinVar contains an entry for this variant (Variation ID: 65995). -

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

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	.;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.9	.;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.82
Sift	Benign	0.38	T;T
Polyphen		1.0	D;D
Vest4		0.80
MutPred		0.82		.;Gain of helix (P = 0.062);
MVP		0.98
MPC		0.62
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.34
gMVP		0.93

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: rs118192134; hg19: chr19-39062822;