chr19-38460461-C-T

Position:

chr19-38460461-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. BS2_SupportingPS4_SupportingBS3_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 proline with leucine at codon 816 of the RYR1 protein, p.(Pro816Leu). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000046, 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). This variant has been identified in one individual with a negative IVCT/CHCT results, BS2_Moderate (The UK (Leeds) MH Unit). Functional studies in HEK293 cells do not show a significant increased sensitivity to RYR1 agonists BS3_Supporting (PMID:31903994). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of .758 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, BS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA063246/MONDO:0018493/012

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:2B:1

Conservation

PhyloP100: 7.91

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 -1 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.

BS3

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.2447C>T	p.Pro816Leu	missense_variant	20/106	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.2447C>T	p.Pro816Leu	missense_variant	20/106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.2447C>T	p.Pro816Leu	missense_variant	20/105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	n.2447C>T		non_coding_transcript_exon_variant	20/80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152242

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251486

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000725

AC:

106

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000881

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:2Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

RYR1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2022

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 816 of the RYR1 protein (p.Pro816Leu). This variant is present in population databases (rs376149732, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (PMID: 31903994, 31994743). ClinVar contains an entry for this variant (Variation ID: 478213). 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. 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. -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 20, 2023

This missense variant replaces proline with leucine at codon 816 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). A functional study has shown that this variant does not increase sensitivity to 4-CmC in HEK293 cells (PMID: 31903994). This variant has been reported in families/individuals affected with malignant hyperthermia susceptibility and in an individual with a negative in vitro contracture test (PMID: 30236257, 31903994, ClinVar: SCV002047609.1). This variant has been identified in 6/282882 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. -

Malignant hyperthermia of anesthesia

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Malignant Hyperthermia Susceptibility Variant Curation Expert Panel, ClinGen

Nov 09, 2021

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 proline with leucine at codon 816 of the RYR1 protein, p.(Pro816Leu). The maximum allele frequency for this variant among the six major gnomAD populations is NFE: .000046, 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). This variant has been identified in one individual with a negative IVCT/CHCT results, BS2_Moderate (The UK (Leeds) MH Unit). Functional studies in HEK293 cells do not show a significant increased sensitivity to RYR1 agonists BS3_Supporting (PMID: 31903994). This variant does not reside in a hotspot for pathogenic variants that contribute to MHS. A REVEL score of .758 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, BS3_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

.;D

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.90

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-9.1

D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.68

MVP

0.94

MPC

1.0

ClinPred

0.91

GERP RS

4.1

Varity_R

0.64

gMVP

0.76

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