rs118192138

chr19-38572221-T-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000540.3(RYR1):c.13949T>C(p.Leu4650Pro) variant causes a missense change. 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L4650L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 5.08

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 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000540.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 19-38572221-T-C is Pathogenic according to our data. Variant chr19-38572221-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38572221-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.13949T>C	p.Leu4650Pro	missense_variant	95/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.13949T>C	p.Leu4650Pro	missense_variant	95/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 06, 2018	The p.Leu4650Pro variant has been previously reported in an affected child who also carried p.Lys4724Gln variant on the other allele (Romero 2003). She was born at 37 weeks of gestation with prenatal history of hydramnion, fetal akinesia and breach presentation. She presented with multiple arthrogryposis, severe hypotonia, amyotrophy and hypomimia, and required respiratory mechanical assistance. Muscle biopsy at two months of age showed type I fiber predominance, unique large eccentric cores, some necrotic or regenerative fibers and connective tissue increase. At age 5, she was reported to have delayed motor development, ptosis and strabismus (Romero 2003). The p.Leu4650Pro variant is listed in ClinVar (Variation ID 65961). Additionally, in vitro functional studies with p.Phe1528Leu demonstrated that this variant results in excitation-contraction uncoupling by reducing channel opening in the absence of a change in calcium ion permeation (Dulhunty et al.) -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

Central core myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

May 11, 2010

- -

RYR1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 03, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects RYR1 function (http://aups.org.au/Proceedings/43/186P/). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. ClinVar contains an entry for this variant (Variation ID: 65961). This missense change has been observed in individuals with clinical features of autosomal recessive congenital myopathy (PMID: 12937085; externalcommunication). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 4650 of the RYR1 protein (p.Leu4650Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Uncertain	23
Dann	Benign	0.94
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.75	T;T
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.89	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;D
Polyphen		0.96	D;D
Vest4		0.93
MutPred		0.93		.;Loss of helix (P = 0.0072);
MVP		0.96
MPC		1.4
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.87
gMVP		0.94

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: rs118192138; hg19: chr19-39062861;