rs147336515

Positions:

chr19-38463522-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The variant NM_000540.3:c.2677G>A in RYR1 is a missense variant predicted to cause substitution of glycine by serine at amino acid 893 (p.Gly893Ser). The highest population minor allele frequency in gnomAD v4.1.1 is 0.005439 (483/75052 alleles) for the African population, which is higher than the ClinGen congenital myopathy RYR1 threshold ( ≥ 0.0000486) for BA1, and therefore meets this criterion (BA1). This variant has been reported in one proband in the literature, who lacked a second allele and presented with type I muscle fiber predominance, proximal, axial, and facial weakness, limited upward gaze, and achilles tendon contracture. However, the father had the variant but was unaffected (PMID:22473935). In summary, the variant meets criteria to be classified as benign for AD RYR1-related myopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen Congenital Myopathies VCEP: BA1. (Congenital Myopathies VCEP specifications version 2; 08/27/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA024360/MONDO:0100150/150

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 9.98

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 Benign. Variant got -8 ACMG points.

BA1

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.2677G>A	p.Gly893Ser	missense_variant	21/106	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.2677G>A	p.Gly893Ser	missense_variant	21/106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.2677G>A	p.Gly893Ser	missense_variant	21/105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	n.2677G>A		non_coding_transcript_exon_variant	21/80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

285

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00666

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.00143

GnomAD3 exomes

AF:

0.000479

AC:

118

AN:

246412

Hom.:

AF XY:

0.000351

AC XY:

AN XY:

133902

show subpopulations

Gnomad AFR exome

AF:

0.00684

Gnomad AMR exome

AF:

0.000174

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:

0.0000447

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000175

AC:

256

AN:

1459416

Hom.:

Cov.:

AF XY:

0.000140

AC XY:

102

AN XY:

726120

show subpopulations

Gnomad4 AFR exome

AF:

0.00613

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.00188

AC:

287

AN:

152332

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

145

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00668

Gnomad4 AMR

AF:

0.000392

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:

0.00142

Alfa

AF:

0.000259

Hom.:

Bravo

AF:

0.00215

ESP6500AA

AF:

0.00499

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000536

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 27, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 23, 2019	Variant summary: RYR1 c.2677G>A (p.Gly893Ser) results in a non-conservative amino acid change located in the first Ryr domain (IPR003032) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 277800 control chromosomes, predominantly at a frequency of 0.007 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2500 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR1 causing Central Core Disease phenotype (2.8e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2677G>A has been reported in the literature in individuals affected with myopathy (Klein_2012, Maggi_2013, Isackson_2018), however one of these patient's unaffected father also tested positive for this variant, supporting a benign role for the variant (Klein_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Malignant hyperthermia, susceptibility to, 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 29, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Congenital multicore myopathy with external ophthalmoplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 29, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

RYR1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 21, 2020

This variant is associated with the following publications: (PMID: 23394784, 24055113, 22473935, 25637381, 26332594) -

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

- -

Congenital myopathy

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.82

.;D

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.045

T;T

MetaSVM

Uncertain

0.79

MutationAssessor

Pathogenic

2.9

M;M

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Pathogenic

0.84

Sift

Benign

0.038

D;D

Polyphen

1.0

D;D

Vest4

0.86

MVP

0.98

MPC

1.0

ClinPred

0.062

GERP RS

4.0

Varity_R

0.76

gMVP

0.82

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