19-38452916-A-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP2PP3_ModeratePP5_Very_Strong

The NM_000540.3(RYR1):c.1342A>T(p.Ile448Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 9.21

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

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, 0.904

PP5

Variant 19-38452916-A-T is Pathogenic according to our data. Variant chr19-38452916-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 571022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38452916-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.1342A>T	p.Ile448Phe	missense_variant	Exon 13 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 link	c.1342A>T	p.Ile448Phe	missense_variant	Exon 13 of 106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 link	c.1342A>T	p.Ile448Phe	missense_variant	Exon 13 of 105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 link	n.1342A>T		non_coding_transcript_exon_variant	Exon 13 of 80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249700

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135302

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461512

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

RYR1-related disorder

Pathogenic:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 448 of the RYR1 protein (p.Ile448Phe). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 28269792, 28818389). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 571022). 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) indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Jul 11, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28818389, Singanamalla2021[CaseReport], 28269792, 33767344) -

Centronuclear myopathy

Pathogenic:1

Mar 01, 2024

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2+PM3+PP2+PP3 -

King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy

Uncertain:1

Jul 03, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.93

.;D

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.3

D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.74

MutPred

0.60

Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);

MVP

0.99

MPC

1.1

ClinPred

0.95

GERP RS

4.5

Varity_R

0.58

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over