rs193922846

Positions:

• chr19-38565283-GTGCGGCGGC-G
• chr19-38565283-GTGCGGCGGC-GTGCGGCGGCTGCGGCGGC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4

The NM_000540.3(RYR1):​c.12960_12968delGCGGCGGCT​(p.Arg4321_Leu4323del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000103 in 1,005,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000095 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: RYR1 NM_000540.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.74

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 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000540.3.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3	c.12960_12968delGCGGCGGCT	p.Arg4321_Leu4323del	disruptive_inframe_deletion	91/106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.12960_12968delGCGGCGGCT	p.Arg4321_Leu4323del	disruptive_inframe_deletion	91/106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.12945_12953delGCGGCGGCT	p.Arg4316_Leu4318del	disruptive_inframe_deletion	90/105	1		ENSP00000347667.3
RYR1	ENST00000689936.1	c.1350_1358delGCGGCGGCT	p.Arg451_Leu453del	disruptive_inframe_deletion	8/22			ENSP00000508999.2
RYR1	ENST00000688602.1	n.1368_1376delGCGGCGGCT		non_coding_transcript_exon_variant	9/23			ENSP00000510767.2

Frequencies

GnomAD3 genomes AF: 0.0000954 AC: 14 AN: 146752 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000978

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000136

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 90 AN: 858338 Hom.: 0 AF XY: 0.0000727 AC XY: 29 AN XY: 398990

Gnomad4 AFR exome AF: 0.000123

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000887

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.0000695

GnomAD4 genome AF: 0.0000954 AC: 14 AN: 146752 Hom.: 0 Cov.: 31 AF XY: 0.0000420 AC XY: 3 AN XY: 71388

Gnomad4 AFR AF: 0.0000978

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000136

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.0000756

Asia WGS AF: 0.000365 AC: 1 AN: 2750

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2024	Identified in a patient with dilated cardiomyopathy in the published literature and reported as a variant of uncertain significance (PMID: 32969603); In-frame deletion of 3 amino acids in a non-repeat region; In silico analysis indicates that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32969603) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 26, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 05, 2015	- -

RYR1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 28, 2022

This variant, c.12960_12968del, results in the deletion of 3 amino acid(s) of the RYR1 protein (p.Arg4321_Leu4323del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.03%). This variant has been observed in individual(s) with nemaline myopathy by muscle biopsy (Invitae). ClinVar contains an entry for this variant (Variation ID: 544390). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Congenital myopathy with fiber type disproportion;C1840365:King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 29, 2021

- -

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: rs193922846; hg19: chr19-39055923;