rs575780192

Positions:

chr19-38499811-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4

The NM_000540.3(RYR1):c.7204C>T(p.Arg2402Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000386 in 1,605,366 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 1 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.39774346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.7204C>T	p.Arg2402Trp	missense_variant	44/106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.7204C>T	p.Arg2402Trp	missense_variant	44/106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.7204C>T	p.Arg2402Trp	missense_variant	44/105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000594335.5 linkuse as main transcript	n.655C>T		non_coding_transcript_exon_variant	5/49	1		ENSP00000470927.2	M0R014
RYR1	ENST00000599547.6 linkuse as main transcript	n.7204C>T		non_coding_transcript_exon_variant	44/80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000132

AC:

AN:

235432

Hom.:

AF XY:

0.000124

AC XY:

AN XY:

128994

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000206

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00123

Gnomad SAS exome

AF:

0.0000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000941

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000372

AC:

AN:

1453114

Hom.:

Cov.:

AF XY:

0.0000443

AC XY:

AN XY:

723076

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000135

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000833

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000998

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Malignant hyperthermia, susceptibility to, 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change is predicted to replace arginine with tryptophan at codon 2402 in exon 44 of the RYR1 protein (p.(Arg2402Trp)). The arginine residue is moderately conserved (100 vertebrates, UCSC), and is located in the RYR1 cytosolic shell. There is a large physicochemical difference between arginine and tryptophan. The variant is present in a large population cohort at a frequency of 0.01% (rs575780192, 34/266,730 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.1% in the east Asian population (25/19,482 alleles in gnomAD v2.1). The variant has been not been reported in RYR1-related disorders in the relevant medical literature, and has been reported as a variant of uncertain significance (ClinVar). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (4/4 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 09, 2024	This missense variant replaces arginine with tryptophan at codon 2402 of the RYR1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. This variant occurs in a region of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 34/266730 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 22, 2023	PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 20681998, 22473935, 16084090, 12668474) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 10, 2015

- -

RYR1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2402 of the RYR1 protein (p.Arg2402Trp). This variant is present in population databases (rs575780192, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with RYR1-related conditions. ClinVar contains an entry for this variant (Variation ID: 212105). 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 with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

0.0015

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

.;D

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.92

D;D

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.40

T;T

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.8

L;L

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.8

D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0040

D;D

Polyphen

1.0

D;D

Vest4

0.73

MutPred

0.41

Loss of solvent accessibility (P = 0.0199);Loss of solvent accessibility (P = 0.0199);

MVP

0.99

MPC

0.58

ClinPred

0.28

GERP RS

1.6

Varity_R

0.43

gMVP

0.82

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

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