rs151119428

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBP6_Strong

The NM_000540.3(RYR1):c.12553G>A(p.Ala4185Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000661 in 1,613,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A4185V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:6B:6

Conservation

PhyloP100: 0.636

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_benign. Variant got -3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000540.3

PP2

Missense variant where missense usually causes diseases, RYR1

BP4

Computational evidence support a benign effect (MetaRNN=0.16345057).

BP6

Variant 19-38561383-G-A is Benign according to our data. Variant chr19-38561383-G-A is described in ClinVar as [Uncertain_significance]. Clinvar id is 224402.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.12553G>A	p.Ala4185Thr	missense_variant	90/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.12553G>A	p.Ala4185Thr	missense_variant	90/106	5	NM_000540.3	A2	P21817-1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.000514

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000308

AC:

AN:

249960

Hom.:

AF XY:

0.000310

AC XY:

AN XY:

135292

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

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:

0.000620

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000693

AC:

1012

AN:

1461158

Hom.:

Cov.:

AF XY:

0.000662

AC XY:

481

AN XY:

726908

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.000862

Gnomad4 OTH exome

AF:

0.000662

GnomAD4 genome

AF:

0.000361

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000515

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000436

Hom.:

Bravo

AF:

0.000366

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000264

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 15, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 20, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2022	Initially reported in an individual with a positive in-vitro contracture test (IVCT) and suspected malignant hyperthermia susceptibility; however, this individual also harbored an additional RYR1 variant and the contribution of A4185T to the phenotype was uncertain (Kravea et al., 2011); Subsequently, A4185T was reported as a variant of uncertain significance in an individual who likely had a malignant hyperthermia episode during surgery, but an IVCT was not performed (MacKay et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27452334, 24195946, 22473935, 27555149, 32236737, 21455645, 31559918) -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 01, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 02, 2018	- -

Malignant hyperthermia of anesthesia

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Apr 06, 2023

This pathogenicity assessment is relevant only for malignant hyperthermia susceptibility (MHS) inherited in an autosomal dominant pattern. Variants in RYR1 can also cause other myopathies inherited in an autosomal dominant pattern or in an autosomal recessive pattern. Some of these disorders may predispose individuals to malignant hyperthermia. RYR1 variants may also contribute to a malignant hyperthermia reaction in combination with other genetic and non-genetic factors and the clinician needs to consider such factors in making management decisions. This sequence variant predicts a substitution of alanine with threonine at codon 4185 of the RYR1 protein, p.(Ala4185Thr). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: 0.000631, a frequency consistent with pathogenicity for MHS. This variant has been reported in four unrelated individuals who have a personal or family history of a malignant hyperthermia reaction, three of these individuals had a positive in vitro contracture test (IVCT) or caffeine halothane contracture test (CHCT) result (if the proband was unavailable for testing, a positive diagnostic test result in a mutation-positive relative was counted) (PMID: 21455645, 30236257, 31559918, 27555149). However, the high MAF in the NFE population in gnomAD precludes the use of PS4. No functional studies were identified for this variant. This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score <0.5 (0.402) supports a benign status for this variant, BP4. This variant has been classified as a Variant of Unknown Significance. Criteria implemented: BP4. -

Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 02, 2022

- -

Congenital multicore myopathy with external ophthalmoplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 02, 2018

- -

Central core myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RYR1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Neuromuscular disease, congenital, with uniform type 1 fiber

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.21

Cadd

Benign

Dann

Benign

0.94

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.27

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.51

MetaRNN

Benign

0.16

T;T

MetaSVM

Uncertain

0.72

MutationTaster

Benign

0.89

D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.7

N;N

REVEL

Uncertain

0.40

Sift

Uncertain

0.026

D;D

Polyphen

0.66

P;P

Vest4

0.36

MVP

0.93

MPC

0.55

ClinPred

0.038

GERP RS

1.2

Varity_R

0.069

gMVP

0.70

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