rs367543055

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate

The NM_000540.3(RYR1):​c.5333C>A​(p.Ser1778*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000411 in 1,461,290 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 Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S1778S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RYR1
NM_000540.3 stop_gained

Scores

3
2
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 4.99
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 19-38485988-C-A is Pathogenic according to our data. Variant chr19-38485988-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 42101.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
RYR1NM_000540.3 linkc.5333C>A p.Ser1778* stop_gained Exon 34 of 106 ENST00000359596.8 NP_000531.2 P21817-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
RYR1ENST00000359596.8 linkc.5333C>A p.Ser1778* stop_gained Exon 34 of 106 5 NM_000540.3 ENSP00000352608.2 P21817-1
RYR1ENST00000355481.8 linkc.5333C>A p.Ser1778* stop_gained Exon 34 of 105 1 ENSP00000347667.3 P21817-2
RYR1ENST00000599547.6 linkn.5333C>A non_coding_transcript_exon_variant Exon 34 of 80 2 ENSP00000471601.2 M0R127

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1461290
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726946
show subpopulations
Gnomad4 AFR exome
AF:
0.00
AC:
0
AN:
33476
Gnomad4 AMR exome
AF:
0.00
AC:
0
AN:
44724
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26126
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39694
Gnomad4 SAS exome
AF:
0.00
AC:
0
AN:
86258
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
52944
Gnomad4 NFE exome
AF:
0.00000540
AC:
6
AN:
1111924
Gnomad4 Remaining exome
AF:
0.00
AC:
0
AN:
60376
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000567
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

RYR1-related disorder Pathogenic:1
Jun 03, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ser1778*) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with RYR1-related conditions (PMID: 20583297). ClinVar contains an entry for this variant (Variation ID: 42101). For these reasons, this variant has been classified as Pathogenic. -

Congenital myopathy with fiber type disproportion Other:1
-
GeneReviews
Significance:not provided
Review Status:no classification provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
38
DANN
Uncertain
0.99
Eigen
Uncertain
0.30
Eigen_PC
Benign
0.0070
FATHMM_MKL
Pathogenic
0.98
D
Vest4
0.68
GERP RS
1.4
Mutation Taster
=1/199
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs367543055; hg19: chr19-38976628; API