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NM_000540.3(RYR1):c.14818G>A (p.Ala4940Thr) AND not provided

Germline classification:
Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:
Mar 8, 2023
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:
RCV000119566.39

Allele description

NM_000540.3(RYR1):c.14818G>A (p.Ala4940Thr)

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.14818G>A (p.Ala4940Thr)
Other names:
NM_000540.2(RYR1):c.14818G>A
HGVS:
  • NC_000019.10:g.38585952G>A
  • NG_008866.1:g.157253G>A
  • NM_000540.3:c.14818G>AMANE SELECT
  • NM_001042723.2:c.14803G>A
  • NP_000531.2:p.Ala4940Thr
  • NP_000531.2:p.Ala4940Thr
  • NP_001036188.1:p.Ala4935Thr
  • LRG_766t1:c.14818G>A
  • LRG_766:g.157253G>A
  • LRG_766p1:p.Ala4940Thr
  • NC_000019.9:g.39076592G>A
  • NM_000540.2:c.14818G>A
  • P21817:p.Ala4940Thr
  • p.(Ala4940Thr)
  • p.A4940T
Protein change:
A4935T
Links:
UniProtKB: P21817#VAR_045780; dbSNP: rs118192158
NCBI 1000 Genomes Browser:
rs118192158
Molecular consequence:
  • NM_000540.3:c.14818G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042723.2:c.14803G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
8

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000154473Leiden Muscular Dystrophy (RYR1)
no classification provided
not providedunknownnot provided

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

SCV000194811Genetic Services Laboratory, University of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2007)
Pathogenic
(Mar 27, 2013)
germlineclinical testing

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

SCV000225118Eurofins Ntd Llc (ga)
criteria provided, single submitter

(EGL Classification Definitions 2015)
Likely pathogenic
(Aug 31, 2017)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV000329509GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Pathogenic
(Mar 12, 2022)
germlineclinical testing

Citation Link,

SCV000852464PreventionGenetics, part of Exact Sciences
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 22, 2018)
germlineclinical testing

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

SCV001715524Mayo Clinic Laboratories, Mayo Clinic
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jun 3, 2019)
germlineclinical testing

PubMed (14)
[See all records that cite these PMIDs]

SCV001961815CeGaT Center for Human Genetics Tuebingen
criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)
Pathogenic
(Nov 1, 2021)
germlineclinical testing

Citation Link,

SCV002019952Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 8, 2023)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownnot providednot providednot providednot provided1not providedliterature only
not providedgermlineyes2not providednot providednot providednot providedclinical testing
not providedgermlineunknown6not providednot providednot providednot providedclinical testing

Citations

PubMed

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee..

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]
PMID:
18414213

Principal mutation hotspot for central core disease and related myopathies in the C-terminal transmembrane region of the RYR1 gene.

Davis MR, Haan E, Jungbluth H, Sewry C, North K, Muntoni F, Kuntzer T, Lamont P, Bankier A, Tomlinson P, Sánchez A, Walsh P, Nagarajan L, Oley C, Colley A, Gedeon A, Quinlivan R, Dixon J, James D, Müller CR, Laing NG.

Neuromuscul Disord. 2003 Feb;13(2):151-7.

PubMed [citation]
PMID:
12565913
See all PubMed Citations (15)

Details of each submission

From Leiden Muscular Dystrophy (RYR1), SCV000154473.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providednot provided PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownnot provided1not providednot providednot providednot providednot providednot provided

From Genetic Services Laboratory, University of Chicago, SCV000194811.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Eurofins Ntd Llc (ga), SCV000225118.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided5not providednot providedclinical testing PubMed (5)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided5not providednot providednot provided

From GeneDx, SCV000329509.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Also reported in a patient with malignant hyperthermia susceptibility (Sambuughin et al., 2005); Published functional studies using transgenic C. elegans with the A4940T variant demonstrate a damaging effect of increased sensitivity to halothane and caffeine, with decreased locomotion (Nicoll Baines et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14670767, 23558838, 12565913, 20301565, 15731587, 12467748, 28325813, 25747005, 23183335, 28687594, 16084090, 1256913, 31321302, 31395954, 31559918, 32403337, 33646171)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From PreventionGenetics, part of Exact Sciences, SCV000852464.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV001715524.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (14)

Description

PS3, PS4_M, PM1, PM2, PP1, PP3, PP4

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From CeGaT Center for Human Genetics Tuebingen, SCV001961815.14

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided2not providednot providednot provided

From Revvity Omics, Revvity, SCV002019952.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024