rs760235443

Positions:

chr19-38469367-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP2

The NM_000540.3(RYR1):c.3619G>A(p.Val1207Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 9.88

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 3 ACMG points.

PM1

In a domain B30.2/SPRY 2 (size 195) in uniprot entity RYR1_HUMAN there are 12 pathogenic changes around while only 3 benign (80%) 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.3619G>A	p.Val1207Met	missense_variant	27/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.3619G>A	p.Val1207Met	missense_variant	27/106	5	NM_000540.3	ENSP00000352608	A2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.3619G>A	p.Val1207Met	missense_variant	27/105	1		ENSP00000347667	P4	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	c.3619G>A	p.Val1207Met	missense_variant, NMD_transcript_variant	27/80	2		ENSP00000471601

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000127

AC:

AN:

251420

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135904

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.0000513

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000844

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	RYR1: PM2:Supporting, PM3:Supporting, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 25, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 10, 2021	- -

Malignant hyperthermia, susceptibility to, 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces valine with methionine at codon 1207 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it has been observed in individuals affected with other phenotype(s) (ClinVar Variation ID: 544419; PMID: 30611313). This variant has been identified in 34/282788 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 19, 2023

Variant summary: RYR1 c.3619G>A (p.Val1207Met) results in a conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251420 control chromosomes (i.e., 32 alleles, no homozygotes; gnomAD v2.1.1. Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3619G>A has been reported in the literature in at least one compound heterozygous individual affected with core-rod myopathy (e.g., Garibaldi_2019) and one homozygous individual affected with distal arthrogryposis (e.g., Shamseldin_2021). These data indicate that the variant may be associated with autosomal recessive disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding an 80% reduction in RyR1 protein levels in a muscle biopsy from a compound heterozgyous patient relative to the control; this finding does not allow convincing conclusions about the variant effect as the measurement was conducted only in the presence of a second RYR1 variant (e.g., Garibaldi_2019). The following publications have been ascertained in the context of this evaluation (PMID: 30611313, 24627108, 34645488, 34316023). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Central core myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

- -

RYR1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2022

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1207 of the RYR1 protein (p.Val1207Met). This variant is present in population databases (rs760235443, gnomAD 0.05%). This missense change has been observed in individual(s) with clinical features of autosomal recessive RYR1-related conditions (PMID: 30611313). ClinVar contains an entry for this variant (Variation ID: 544419). 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;C0751951:Central core myopathy;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

.;D

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-2.1

N;N

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0060

D;D

Polyphen

1.0

D;D

Vest4

0.58

MutPred

0.47

Gain of disorder (P = 0.1398);Gain of disorder (P = 0.1398);

MVP

0.99

MPC

1.0

ClinPred

0.30

GERP RS

3.6

Varity_R

0.18

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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