rs193922893

Positions:

• chr19-38585066-TTCGTCA-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM4 PP3 PP5_Moderate

The NM_000540.3(RYR1):​c.14779_14784del​(p.Val4927_Ile4928del) variant causes a inframe deletion 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 (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: RYR1 NM_000540.3 inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 9.29

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a transmembrane_region Helical; Name=6 (size 20) in uniprot entity RYR1_HUMAN there are 17 pathogenic changes around while only 0 benign (100%) in NM_000540.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000540.3.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 19-38585066-TTCGTCA-T is Pathogenic according to our data. Variant chr19-38585066-TTCGTCA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 66001.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-38585066-TTCGTCA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.14779_14784del	p.Val4927_Ile4928del	inframe_deletion	102/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.14779_14784del	p.Val4927_Ile4928del	inframe_deletion	102/106	5	NM_000540.3	ENSP00000352608	A2

Frequencies

GnomAD3 genomes Cov.: 29

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

GnomAD4 genome Cov.: 29

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 15, 2017	- -
not provided, no classification provided	literature only	Leiden Muscular Dystrophy (RYR1)	-	- -

Central core myopathy Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

May 11, 2010

- -

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: rs193922893; hg19: chr19-39075706;