rs756138074

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PP2PP3_ModeratePP5_Very_Strong

The NM_000540.3(RYR1):c.3362A>G(p.Tyr1121Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

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

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 1.60

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 Pathogenic. Variant got 13 ACMG points.

PM1

In a domain B30.2/SPRY 2 (size 195) in uniprot entity RYR1_HUMAN there are 22 pathogenic changes around while only 9 benign (71%) in NM_000540.3

PP2

Missense variant where missense usually causes diseases, RYR1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

PP5

Variant 19-38467793-A-G is Pathogenic according to our data. Variant chr19-38467793-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38467793-A-G is described in Lovd as [Likely_pathogenic]. Variant chr19-38467793-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.3362A>G	p.Tyr1121Cys	missense_variant	25/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.3362A>G	p.Tyr1121Cys	missense_variant	25/106	5	NM_000540.3	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.3362A>G	p.Tyr1121Cys	missense_variant	25/105	1		P4	P21817-2
RYR1	ENST00000594111.1 linkuse as main transcript	n.455A>G		non_coding_transcript_exon_variant	2/2	2
RYR1	ENST00000599547.6 linkuse as main transcript	c.3362A>G	p.Tyr1121Cys	missense_variant, NMD_transcript_variant	25/80	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00000796

AC:

AN:

251100

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135786

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727204

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:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2015

- -

RYR1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1121 of the RYR1 protein (p.Tyr1121Cys). This variant is present in population databases (rs756138074, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive congenital myopathy (PMID: 20839240, 32403337, 33333461, 33458582). ClinVar contains an entry for this variant (Variation ID: 420141). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on RYR1 protein function. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 22, 2021

Identified in trans with a second RYR1 variant in a patient with congenital myopathy with central nuclei in the published literature (Wilmshurst et al., 2010); Identified with a second RYR1 variant in individuals suspected of having central core disease (Galleni Leao et al., 2020) and congenital myopathy (Gonzalez-Quereda et al., 2020), however it is unknown whether the variants occurred on the same (in cis) or opposite (in trans) chromosomes; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 420141; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 23919265, 32403337, 33333461, 33458582, 20839240) -

Myopathy, RYR1-associated

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 11, 2024

Variant summary: RYR1 c.3362A>G (p.Tyr1121Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251100 control chromosomes. c.3362A>G has been reported in the literature in individuals affected with Myopathy, RYR1-Associated. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32403337, 33458582, 20839240). ClinVar contains an entry for this variant (Variation ID: 420141). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.21

Cadd

Uncertain

Dann

Uncertain

0.99

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.1

D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.85

MutPred

0.78

Loss of phosphorylation at Y1121 (P = 0.03);Loss of phosphorylation at Y1121 (P = 0.03);

MVP

0.94

MPC

1.2

ClinPred

0.99

GERP RS

3.5

Varity_R

0.69

gMVP

0.92

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