Genetic Variant RYR1:p.Phe12Leu (chr19-38433863-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000540.3(RYR1):c.34T>C(p.Phe12Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000066 in 151,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. F12F) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.24

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.34T>C	p.Phe12Leu	missense_variant	Exon 1 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 link	c.34T>C	p.Phe12Leu	missense_variant	Exon 1 of 106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 link	c.34T>C	p.Phe12Leu	missense_variant	Exon 1 of 105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 link	n.34T>C		non_coding_transcript_exon_variant	Exon 1 of 80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151618

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151618

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74024

show subpopulations

Gnomad4 AFR

AF:

0.0000242

AC:

0.0000242342

AN:

0.0000242342

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

RYR1-related disorder

Uncertain:1

Aug 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. 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 not expected to disrupt RYR1 protein function. This variant has not been reported in the literature in individuals affected with RYR1-related conditions. This variant is present in population databases (rs370115856, gnomAD 0.01%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 12 of the RYR1 protein (p.Phe12Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

.;D

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Benign

1.3

L;L

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0020

D;D

Polyphen

0.95

P;B

Vest4

0.70

MutPred

0.77

Gain of disorder (P = 0.0593);Gain of disorder (P = 0.0593);

MVP

0.98

MPC

0.45

ClinPred

0.98

GERP RS

4.8

Varity_R

0.76

gMVP

0.69

Mutation Taster

=25/75

disease causing

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