rs796065337

Positions:

• chr19-38565193-GCCACGGCGGC-GT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP3

The NM_000540.3(RYR1):​c.12860_12869delinsT​(p.Ala4287_Ala4290delinsVal) variant causes a protein altering change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR1 NM_000540.3 protein_altering
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 1.85

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_000540.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.12860_12869delinsT	p.Ala4287_Ala4290delinsVal	protein_altering_variant	91/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.12860_12869delinsT	p.Ala4287_Ala4290delinsVal	protein_altering_variant	91/106	5	NM_000540.3	A2

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2021	In-frame deletion of 4 amino acids and insertion of 1 amino acid in a non-repeat region In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	May 24, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 11, 2014	- -

Central core myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

RYR1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 08, 2016

This sequence change deletes 10 nucleotides and inserts 1 nucleotide into exon 91 of the RYR1 mRNA (c.12860_12869delinsT). This leads to the deletion of amino acids 4287-4290 and the insertion of 1 amino acid (valine) in the RYR1 protein (p.Ala4287_Ala4290delinsVal), but otherwise preserves the integrity of the reading frame. While this variant is present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in an individual with a RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 199216). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted and inserted amino acids is currently unknown. This missense change is located in the C-terminal mutational hotspot of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). In summary, this is a rare variant with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Malignant hyperthermia of anesthesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Multiminicore myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Neuromuscular disease, congenital, with uniform type 1 fiber Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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: rs796065337; hg19: chr19-39055834;