NM_000540.3(RYR1):c.7902C>A (p.Asn2634Lys) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Oct 4, 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:: RCV001356636.5

Allele description [Variation Report for NM_000540.3(RYR1):c.7902C>A (p.Asn2634Lys)]

NM_000540.3(RYR1):c.7902C>A (p.Asn2634Lys)

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.7902C>A (p.Asn2634Lys)

HGVS:

NC_000019.10:g.38502946C>A
NG_008866.1:g.74247C>A
NM_000540.3:c.7902C>AMANE SELECT
NM_001042723.2:c.7902C>A
NP_000531.2:p.Asn2634Lys
NP_000531.2:p.Asn2634Lys
NP_001036188.1:p.Asn2634Lys
LRG_766t1:c.7902C>A
LRG_766:g.74247C>A
LRG_766p1:p.Asn2634Lys
NC_000019.9:g.38993586C>A
NM_000540.2:c.7902C>A

Protein change:

N2634K

Links:

dbSNP: rs148041292

NCBI 1000 Genomes Browser:

rs148041292

Molecular consequence:

NM_000540.3:c.7902C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.7902C>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001551860	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV003195002	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jul 20, 2022)	germline	clinical testing	Citation Link,
SCV003814436	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 4, 2023)	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

SCV001551860

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided

Uncertain significance

unknown

clinical testing

SCV003195002

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jul 20, 2022)

germline

clinical testing

Citation Link,

SCV003814436

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 4, 2023)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001551860.1

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

Description

The RYR1 p.Asn2634Lys variant was not identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs148041292) Clinvitae, LOVD 3.0 and ClinVar (reported as a VUS by the Clinical Molecular Genetics Laboratory at John's Hopkins All Children's Hospital and by the ClinSeq Biesecker Lab at NIH for susceptibility to malignant hyperthermia). The variant was identified in control databases in 38 of 280230 chromosomes at a frequency of 0.000136 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 30 of 129078 chromosomes (freq: 0.000232), Latino in 7 of 35436 chromosomes (freq: 0.000198) and other in 1 of 7206 chromosomes (freq: 0.000139); it was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The RYR1 p.Asn2634Lys variant was found in an unaffected individual in a study analyzing 870 control participants for variants in genes related to malignant hyperthermia susceptibility (Gonsalves_2014_PMID: 24195946). The p.Asn2634 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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

From GeneDx, SCV003195002.1

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

#	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 Revvity Omics, Revvity, SCV003814436.2

#	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: Oct 8, 2024

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