chr19-38561402-G-A

Position:

chr19-38561402-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_000540.3(RYR1):c.12572G>A(p.Arg4191His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,530 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 9.92

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 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.12572G>A	p.Arg4191His	missense_variant	90/106	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.12572G>A	p.Arg4191His	missense_variant	90/106	5	NM_000540.3	ENSP00000352608	A2	P21817-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000805

AC:

AN:

248472

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134742

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460530

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726660

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

RYR1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 25, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 4191 of the RYR1 protein (p.Arg4191His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of autosomal recessive RYR1-related myopathy (PMID: 36131268). ClinVar contains an entry for this variant (Variation ID: 590406). 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) performed at Invitae indicates that this missense variant is expected to disrupt RYR1 protein function with a positive predictive value of 95%. 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. -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 07, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.86

.;D

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-4.2

D;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.68

MutPred

0.57

.;Loss of MoRF binding (P = 0.0075);

MVP

1.0

MPC

0.71

ClinPred

0.98

GERP RS

3.4

Varity_R

0.54

gMVP

0.94

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