NM_000540.3(RYR1):c.14918C>T (p.Pro4973Leu) AND not provided

Germline classification:: Likely pathogenic (6 submissions)
Last evaluated:: Feb 20, 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:: RCV000119571.47

Allele description [Variation Report for NM_000540.3(RYR1):c.14918C>T (p.Pro4973Leu)]

NM_000540.3(RYR1):c.14918C>T (p.Pro4973Leu)

Gene:

RYR1:ryanodine receptor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.2

Genomic location:

Preferred name:

NM_000540.3(RYR1):c.14918C>T (p.Pro4973Leu)

Other names:

NM_000540.2(RYR1):c.14918C>T(p.Pro4973Leu); NM_001042723.1(RYR1):c.14903C>T(p.Pro4968Leu); NM_000540.3(RYR1):c.14918C>T

HGVS:

NC_000019.10:g.38586140C>T
NG_008866.1:g.157441C>T
NM_000540.3:c.14918C>TMANE SELECT
NM_001042723.2:c.14903C>T
NP_000531.2:p.Pro4973Leu
NP_000531.2:p.Pro4973Leu
NP_001036188.1:p.Pro4968Leu
LRG_766t1:c.14918C>T
LRG_766:g.157441C>T
LRG_766p1:p.Pro4973Leu
NC_000019.9:g.39076780C>T
NM_000540.2:c.14918C>T
NM_000540.3:c.14918C>T
P21817:p.Pro4973Leu
p.(Pro4973Leu)

Protein change:

P4968L

Links:

UniProtKB: P21817#VAR_045782; dbSNP: rs146876145

NCBI 1000 Genomes Browser:

rs146876145

Molecular consequence:

NM_000540.3:c.14918C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14903C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000154478	Leiden Muscular Dystrophy (RYR1)	no classification provided	not provided	unknown	not provided	PubMed (1) [See all records that cite this PMID]
SCV000225123	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely pathogenic (Dec 19, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 12208234, 12411788, 23558838 Citation Link,
SCV000596912	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 25, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001872859	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Feb 20, 2024)	germline	clinical testing	Citation Link,
SCV001961816	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Aug 1, 2022)	germline	clinical testing	Citation Link,
SCV002019099	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 26, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

Mutations in the RYR1 gene in Italian patients at risk for malignant hyperthermia: evidence for a cluster of novel mutations in the C-terminal region.

Galli L, Orrico A, Cozzolino S, Pietrini V, Tegazzin V, Sorrentino V.

Cell Calcium. 2002 Sep;32(3):143-51.

PubMed [citation]

PMID:: 12208234

Presence of two different genetic traits in malignant hyperthermia families: implication for genetic analysis, diagnosis, and incidence of malignant hyperthermia susceptibility.

Monnier N, Krivosic-Horber R, Payen JF, Kozak-Ribbens G, Nivoche Y, Adnet P, Reyford H, Lunardi J.

Anesthesiology. 2002 Nov;97(5):1067-74.

PubMed [citation]

PMID:: 12411788

See all PubMed Citations (4)

Details of each submission

From Leiden Muscular Dystrophy (RYR1), SCV000154478.1

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

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

From Eurofins Ntd Llc (ga), SCV000225123.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (3)

#	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		2	not provided	not provided	not provided

From Genetic Services Laboratory, University of Chicago, SCV000596912.1

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

#	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

From GeneDx, SCV001872859.5

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

Description

Reported in individuals in multiple unrelated families who were either malignant hyperthermia susceptible or equivocal by contracture testing (PMID: 12208234, 12411788, 16163667, 30236257); Observed with a variant on the opposite allele (in trans) in a patient with arthrogryposis multiplex congenita in published literature (PMID: 29169929); Found to be on the same chromsome (in cis) as another RYR1 variant and in trans with a third RYR1 variant in an individual with centronuclear myopathy (PMID: 25957634); Published functional studies demonstrate this variant reduces the threshold for store overload-induced calcium release (PMID: 28687594); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23558838, 20681998, 28008009, 30236257, 25637381, 12411788, 16163667, 33087929, 31447099, 32528171, 34008892, 34904211, 35428369, 37919205, 35980353, 28687594, 12208234, 33767344, 25957634, 29169929, 35414440, 37510298)

#	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

From CeGaT Center for Human Genetics Tuebingen, SCV001961816.20

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

Description

RYR1: PM1, PP1, PP3, PS3:Supporting, PS4:Supporting

#	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		2	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002019099.3

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

#	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

Last Updated: Nov 24, 2024

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