chr19-38460397-C-T

Position:

chr19-38460397-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP2PP3

The NM_000540.3(RYR1):c.2383C>T(p.Arg795Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,614,128 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000080 ( 1 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11

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 Uncertain_significance. Variant got 4 ACMG points.

PM1

In a domain B30.2/SPRY 1 (size 216) in uniprot entity RYR1_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000540.3

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.2383C>T	p.Arg795Cys	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.2383C>T	p.Arg795Cys	missense_variant	20/106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.2383C>T	p.Arg795Cys	missense_variant	20/105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	n.2383C>T		non_coding_transcript_exon_variant	20/80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

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:

0.000147

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251486

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000800

AC:

117

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000770

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000764

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000250

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000254

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Etarhuni2024) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	RYR1: PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 23, 2021	- -

Central core myopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 30, 2022	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 24, 2024

Variant summary: RYR1 c.2383C>T (p.Arg795Cys) results in a non-conservative amino acid change located in the B30.2/SPRY domain (IPR001870) 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 9.1e-05 in 251486 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RYR1 causing Myopathy, RYR1-Associated, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2383C>T in individuals affected with Myopathy, RYR1-Associated and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 478212). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Congenital multicore myopathy with external ophthalmoplegia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

RYR1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 795 of the RYR1 protein (p.Arg795Cys). This variant is present in population databases (rs547608972, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of RYR1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 478212). 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. 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. -

Congenital myopathy with fiber type disproportion

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 23, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.065

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

.;D

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Uncertain

0.22

MutationAssessor

Pathogenic

3.2

M;M

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-6.7

D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0070

D;D

Polyphen

1.0

D;D

Vest4

0.80

MVP

0.84

MPC

1.2

ClinPred

0.67

GERP RS

3.8

Varity_R

0.47

gMVP

0.63

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