chr19-38467655-G-A

Position:

chr19-38467655-G-A

Variant summary

Our verdict is Likely benign. Variant got 0 ACMG points: 1P and 1B. PS4_SupportingBS2_Supporting

This summary comes from the ClinGen Evidence Repository: 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 arginine with glutamine at codon 1075 of the RYR1 protein, p.(Arg1075Gln). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000029, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and 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), PS4_Supporting (PMID:30236257). One relative was shown to be heterozygous for the variant and IVCT negative, BS2_Moderate was implemented (PMID:19454545). 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 of 0.846 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID:29300386). Criteria implemented: PS4_Supporting, BS2_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA064575/MONDO:0018493/012

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel P:3U:1B:1

Conservation

PhyloP100: 9.94

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 0 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.3224G>A	p.Arg1075Gln	missense_variant	25/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.3224G>A	p.Arg1075Gln	missense_variant	25/106	5	NM_000540.3	ENSP00000352608	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.3224G>A	p.Arg1075Gln	missense_variant	25/105	1		ENSP00000347667	P4	P21817-2
RYR1	ENST00000594111.1 linkuse as main transcript	n.317G>A		non_coding_transcript_exon_variant	2/2	2
RYR1	ENST00000599547.6 linkuse as main transcript	c.3224G>A	p.Arg1075Gln	missense_variant, NMD_transcript_variant	25/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251480

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00000342

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727242

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:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:3Uncertain:1Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

RYR1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1075 of the RYR1 protein (p.Arg1075Gln). This variant is present in population databases (rs749040743, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive centronuclear myopathy (PMID: 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: 433176). 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%. This variant disrupts the p.Arg1075 amino acid residue in RYR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23826317; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Centronuclear myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

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

Mar 01, 2024

PM2+PM5+PP1+PP2+PP3 -

Arthrogryposis multiplex congenita

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center of Genomic medicine, Geneva, University Hospital of Geneva

May 16, 2017

This RYR2 variant was found in compound heterozygosity with one another RYR2 variant in a fetus with polymalformative syndrome and arthrogryposis -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Mar 09, 2023

This missense variant replaces arginine with glutamine at codon 1075 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a family affected with malignant hyperthermia susceptibility, in two affected individuals and one unaffected individual (PMID: 19454545, 30236257). This variant has also been associated with other phenotypes (ClinVar Variation ID: 433176, PMID: 28818389). This variant has been identified in 1/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. -

Malignant hyperthermia of anesthesia

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Mar 14, 2022

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 arginine with glutamine at codon 1075 of the RYR1 protein, p.(Arg1075Gln). The maximum allele frequency for this variant among the six major gnomAD populations is AMR: 0.000029, a frequency consistent with pathogenicity for MHS. This variant has been reported in an individual with a personal or family history of an MH episode and 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), PS4_Supporting (PMID:30236257). One relative was shown to be heterozygous for the variant and IVCT negative, BS2_Moderate was implemented (PMID: 19454545). 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 of 0.846 supports neither a pathogenic nor a benign status for this variant. Based on using Bayes to combine criteria this variant is assessed as Likely Benign, (PMID: 29300386). Criteria implemented: PS4_Supporting, BS2_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

.;D

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Pathogenic

0.76

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.70

MutPred

0.47

Loss of MoRF binding (P = 0.0241);Loss of MoRF binding (P = 0.0241);

MVP

1.0

MPC

1.1

ClinPred

0.99

GERP RS

2.9

Varity_R

0.71

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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