rs1555785771

Variant names:

• chr19-38506520-A-AG
• rs1555785771
• NM_000540.3:c.8667dupG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000540.3(RYR1):​c.8667dupG​(p.Lys2890GlufsTer53) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RYR1 NM_000540.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.00

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 19-38506520-A-AG is Pathogenic according to our data. Variant chr19-38506520-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 478293.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.8667dupG	p.Lys2890GlufsTer53	frameshift_variant	Exon 56 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.8667dupG	p.Lys2890GlufsTer53	frameshift_variant	Exon 56 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.8667dupG	p.Lys2890GlufsTer53	frameshift_variant	Exon 56 of 105	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.2118dupG		non_coding_transcript_exon_variant	Exon 17 of 49	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.8667dupG		non_coding_transcript_exon_variant	Exon 56 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

RYR1-related disorder Pathogenic:1

Nov 05, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 20583297, 23919265). This sequence change creates a premature translational stop signal (p.Lys2890Glufs*53) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 478293). -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1555785771; hg19: chr19-38997160;