NM_000540.3(RYR1):c.8342_8343del (p.Ile2781fs) AND RYR1-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 25, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001209505.8

Allele description [Variation Report for NM_000540.3(RYR1):c.8342_8343del (p.Ile2781fs)]

NM_000540.3(RYR1):c.8342_8343del (p.Ile2781fs)

Genes:

LOC126862902:BRD4-independent group 4 enhancer GRCh37_chr19:38995830-38997029 [Gene]
RYR1:ryanodine receptor 1 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

19q13.2

Genomic location:

Preferred name:

NM_000540.3(RYR1):c.8342_8343del (p.Ile2781fs)

Other names:

NM_000540.3(RYR1):c.8342_8343del; p.Ile2781fs

HGVS:

NC_000019.10:g.38505340_38505341del
NG_008866.1:g.76641_76642del
NG_087399.1:g.251_252del
NM_000540.3:c.8342_8343delMANE SELECT
NM_001042723.2:c.8342_8343del
NP_000531.2:p.Ile2781Argfs
NP_000531.2:p.Ile2781fs
NP_000531.2:p.Ile2781fs
NP_001036188.1:p.Ile2781fs
LRG_766t1:c.8342_8343del
LRG_766:g.76641_76642del
LRG_766p1:p.Ile2781fs
NC_000019.9:g.38995979_38995980del
NC_000019.9:g.38995980_38995981del
NM_000540.2:c.8342_8343del
NM_000540.2:c.8342_8343delTA

Protein change:

I2781fs

Links:

OMIM: 180901.0037; dbSNP: rs758580075

NCBI 1000 Genomes Browser:

rs758580075

Molecular consequence:

NM_000540.3:c.8342_8343del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001042723.2:c.8342_8343del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: RYR1-related disorder
Synonyms:: RYR1-Related Disorders; RYR1-related condition
Identifiers:: MedGen: CN239331

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001380942	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 23919265, 25960145, 28818389, 30611313, 20839240, 21062345, 28492532
SCV004046371	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001380942

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 25, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004046371

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genotype-phenotype correlations in recessive RYR1-related myopathies.

Amburgey K, Bailey A, Hwang JH, Tarnopolsky MA, Bonnemann CG, Medne L, Mathews KD, Collins J, Daube JR, Wellman GP, Callaghan B, Clarke NF, Dowling JJ.

Orphanet J Rare Dis. 2013 Aug 6;8:117. doi: 10.1186/1750-1172-8-117.

PubMed [citation]

PMID:: 23919265
PMCID:: PMC3751094

Snoeck M, van Engelen BG, Küsters B, Lammens M, Meijer R, Molenaar JP, Raaphorst J, Verschuuren-Bemelmans CC, Straathof CS, Sie LT, de Coo IF, van der Pol WL, de Visser M, Scheffer H, Treves S, Jungbluth H, Voermans NC, Kamsteeg EJ.

Eur J Neurol. 2015 Jul;22(7):1094-112. doi: 10.1111/ene.12713. Epub 2015 May 11.

PubMed [citation]

PMID:: 25960145

See all PubMed Citations (8)

Details of each submission

From Invitae, SCV001380942.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change creates a premature translational stop signal (p.Ile2781Argfs*49) in the RYR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RYR1 are known to be pathogenic (PMID: 23919265, 25960145, 28818389, 30611313). This variant is present in population databases (rs758580075, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 20839240, 21062345). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 590611). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego, SCV004046371.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This frameshifting variant in exon 53 of 106 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in patients with congenital myopathy with central nuclei (PMID: 21062345, 30611313, 20839240). The c.8342_8343del (p.Ile2781ArgfsTer49) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (5/280914) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.8342_8343del (p.Ile2781ArgfsTer49) variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 19, 2024

ClinVar

Relating variation to medicine