rs1057518970

Positions:

chr19-38448398-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP2PP3_Strong

The NM_000540.3(RYR1):c.844C>T(p.Arg282Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,612,336 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R282Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.27

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000540.3

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, 0.952

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.844C>T	p.Arg282Trp	missense_variant	10/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.844C>T	p.Arg282Trp	missense_variant	10/106	5	NM_000540.3	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.844C>T	p.Arg282Trp	missense_variant	10/105	1		P4	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	c.844C>T	p.Arg282Trp	missense_variant, NMD_transcript_variant	10/80	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249486

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135104

show subpopulations

Gnomad AFR exome

AF:

0.0000617

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1460110

Hom.:

Cov.:

AF XY:

0.00000964

AC XY:

AN XY:

726386

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Myopathy;C0035229:Respiratory insufficiency;C0699743:Congenital muscular dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 21, 2014

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Jan 01, 2019

- -

RYR1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2023

The RYR1 c.844C>T variant is predicted to result in the amino acid substitution p.Arg282Trp. This variant was reported in the compound heterozygous state in a fetus with isolated hydrops fetalis (Table S1, case 166, Fu et al. 2022. PubMed ID: 36307859) and in a fetus with non-immune hydrops fetalis with a loss-of-function RYR1 variant as well as as loss-of-function variant in SOX18 (Zhang et al. 2021. PubMed ID: 34625927). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 03, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

.;D

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Uncertain

2.8

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-6.0

D;D

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.83

MutPred

0.73

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);

MVP

0.99

MPC

1.0

ClinPred

0.99

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.80

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