NM_000540.3(RYR1):c.7844G>A (p.Arg2615His) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jul 11, 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:: RCV000721676.9

Allele description [Variation Report for NM_000540.3(RYR1):c.7844G>A (p.Arg2615His)]

NM_000540.3(RYR1):c.7844G>A (p.Arg2615His)

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.7844G>A (p.Arg2615His)

HGVS:

NC_000019.10:g.38502888G>A
NG_008866.1:g.74189G>A
NM_000540.3:c.7844G>AMANE SELECT
NM_001042723.2:c.7844G>A
NP_000531.2:p.Arg2615His
NP_000531.2:p.Arg2615His
NP_001036188.1:p.Arg2615His
LRG_766t1:c.7844G>A
LRG_766:g.74189G>A
LRG_766p1:p.Arg2615His
NC_000019.9:g.38993528G>A
NM_000540.2:c.7844G>A

Protein change:

R2615H

Links:

dbSNP: rs145183043

NCBI 1000 Genomes Browser:

rs145183043

Molecular consequence:

NM_000540.3:c.7844G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.7844G>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
SCV001551029	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
SCV004021631	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jul 11, 2023)	germline	clinical testing	Citation Link,
SCV004236906	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 16, 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

SCV001551029

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

SCV004021631

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jul 11, 2023)

germline

clinical testing

Citation Link,

SCV004236906

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 16, 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	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
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), SCV001551029.1

#	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.Arg2615His variant was not identified in the literature but was identified in dbSNP (ID: rs145183043) and ClinVar (classified as uncertain significance by Invitae and Prevention Genetics). The variant was identified in control databases in 21 of 280550 chromosomes at a frequency of 0.00007485 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 6 of 24906 chromosomes (freq: 0.000241), East Asian in 3 of 19924 chromosomes (freq: 0.000151), Latino in 5 of 35422 chromosomes (freq: 0.000141), Other in 1 of 7210 chromosomes (freq: 0.000139), European (non-Finnish) in 5 of 128914 chromosomes (freq: 0.000039) and South Asian in 1 of 30610 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish or European (Finnish) populations. The p.Arg2615 residue is not 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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, SCV004021631.1

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

Description

Observed in patient with congenital axial hypotonia and normal serum CK in published literature (Gonzalez-Quereda et al., 2020); however, no further clinical information was provided.; 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: 32403337)

#	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, SCV004236906.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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