19-38585055-C-A

Position:

• chr19-38585055-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000540.3(RYR1):​c.14759C>A​(p.Thr4920Asn) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.90

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 11 ACMG points.

• PM1: In a topological_domain Lumenal (size 19) in uniprot entity RYR1_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000540.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the RYR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 94 curated benign missense variants. Gene score misZ: 1.918 (below the threshold of 3.09). Trascript score misZ: 3.9788 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.966
• PP5: Variant 19-38585055-C-A is Pathogenic according to our data. Variant chr19-38585055-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65997.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-38585055-C-A is described in Lovd as [Pathogenic]. Variant chr19-38585055-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.14759C>A	p.Thr4920Asn	missense_variant	102/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.14759C>A	p.Thr4920Asn	missense_variant	102/106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

Alfa AF: 0.00152 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

RYR1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 16, 2024

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 4920 of the RYR1 protein (p.Thr4920Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant central core disease and/or central core disease (PMID: 16621918, 27363342; internal data). ClinVar contains an entry for this variant (Variation ID: 65997). Invitae Evidence 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 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. This variant disrupts the p.Thr4920 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16621918, 27363342). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Central core myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

May 11, 2010

- -

not provided Other:1

not provided, no classification provided

literature only

RYR1 database

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.97	.;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	.;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.0	D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.83		.;Loss of sheet (P = 0.1158);
MVP		0.98
MPC		0.65
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.97
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: rs118192155; hg19: chr19-39075695;