rs200950673

Positions:

chr19-38517386-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP6

The NM_000540.3(RYR1):c.9713A>G(p.Glu3238Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000321 in 1,613,676 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:8

Conservation

PhyloP100: 9.27

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 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.

BP6

Variant 19-38517386-A-G is Benign according to our data. Variant chr19-38517386-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161365.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=4, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.9713A>G	p.Glu3238Gly	missense_variant	66/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.9713A>G	p.Glu3238Gly	missense_variant	66/106	5	NM_000540.3	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.9713A>G	p.Glu3238Gly	missense_variant	66/105	1		P4	P21817-2
RYR1	ENST00000594335.5 linkuse as main transcript	c.*456A>G		3_prime_UTR_variant, NMD_transcript_variant	26/49	1
RYR1	ENST00000599547.6 linkuse as main transcript	c.*472A>G		3_prime_UTR_variant, NMD_transcript_variant	65/80	2

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

151804

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000257

AC:

AN:

248662

Hom.:

AF XY:

0.000304

AC XY:

AN XY:

134722

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:

0.00114

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000234

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000334

AC:

488

AN:

1461754

Hom.:

Cov.:

AF XY:

0.000360

AC XY:

262

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00108

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000325

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000197

AC:

AN:

151922

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000832

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000218

Hom.:

Bravo

AF:

0.000162

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000321

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2020	Reported in an individual with late-onset myopathy in the published literature (Loseth et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25637381, 23329375, 25747005, 23558838) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 21, 2015	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 25, 2017	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in one patient with axial myopathy and one who is malignant hyperthermia susceptible as determined by the Caffeine contracture test. The variant has a Max MAF of 0.1% in ExAC (19 South Asian alleles) and 0.1% in gnomAD (35 South Asian alleles). Frequency is too high for disease. It is classified with 1 star in ClinVar as VUS by GeneDx and as Likely benign by CSER_CC_NCGL. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 29, 2024	- -

Axial myopathy, late-onset

Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Malignant hyperthermia, susceptibility to, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Malignant hyperthermia of anesthesia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Multiminicore myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Uncertain

0.39

BayesDel_addAF

Benign

-0.0079

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Uncertain

0.79

.;D

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.73

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Uncertain

0.52

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.3

D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.017

D;D

Polyphen

0.88

P;P

Vest4

0.72

MVP

0.93

MPC

0.38

ClinPred

0.50

GERP RS

4.2

Varity_R

0.45

gMVP

0.69

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