rs794727683

Positions:

• chr19-38500834-GCAGCCAAAGATGT-G

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.7463_7475delCAAAGATGTCAGC​(p.Pro2488fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: RYR1 NM_000540.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.31

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 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 19-38500834-GCAGCCAAAGATGT-G is Pathogenic according to our data. Variant chr19-38500834-GCAGCCAAAGATGT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 197559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38500834-GCAGCCAAAGATGT-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.7463_7475delCAAAGATGTCAGC	p.Pro2488fs	frameshift_variant	47/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.7463_7475delCAAAGATGTCAGC	p.Pro2488fs	frameshift_variant	47/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.7463_7475delCAAAGATGTCAGC	p.Pro2488fs	frameshift_variant	47/105	1		ENSP00000347667.3
RYR1	ENST00000594335.5	n.914_926delCAAAGATGTCAGC		non_coding_transcript_exon_variant	8/49	1		ENSP00000470927.2
RYR1	ENST00000599547.6	n.7463_7475delCAAAGATGTCAGC		non_coding_transcript_exon_variant	47/80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 25, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2014	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs794727683; hg19: chr19-38991474;