rs193922887

Positions:

• chr19-38584963-C-A
• chr19-38584963-C-G
• chr19-38584963-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000540.3(RYR1):​c.14667C>A​(p.Tyr4889*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,792 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RYR1 NM_000540.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.63

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-38584963-C-A is Pathogenic according to our data. Variant chr19-38584963-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 647148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.14667C>A	p.Tyr4889*	stop_gained	102/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.14667C>A	p.Tyr4889*	stop_gained	102/106	5	NM_000540.3	ENSP00000352608.2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461792 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

RYR1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 15, 2020

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 20583297, 23919265). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This truncation has been observed in the heterozygous state in a family affected with congenital myopathy; however, the full gene was not sequenced and the clinical significance of this variant in autosomal dominant RYR1-related conditions is currently unknown (PMID: 17483490). ClinVar contains an entry for this variant (Variation ID: 647148). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr4889*) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. -

Central core myopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Nov 15, 2018

This nonsense variant found in exon 102 of 106 is predicted to result in loss of normal protein function. This variant has not been previously reported to our knowledge, however, a different variant involving the same nucleotide (c.14667C>G (p.Tyr4889Ter)) has been reported as a heterozygous change in a patient with childhood-onset myopathy (PMID: 21911697, 17483490). Although the reported c.14667C>G variant is also predicted to result in a premature termination codon, RNA studies performed on muscle tissue from the affected patient indicated that the c.14667C>G variant leads to creation of a novel splice site resulting in an in-frame deletion of the first 21 nucleotides of exon 102 (PMID: 17483490). The c.14667C>A (p.Tyr4889Ter) variant detected in this individual is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.14667C>A (p.Tyr4889Ter) variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	37
DANN	Uncertain	0.98
Eigen	Benign	0.10
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.49	N
Vest4		0.88
GERP RS		-1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193922887; hg19: chr19-39075603;