NM_001035.3(RYR2):c.8209-3A>G AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Sep 24, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000036795.4

Allele description [Variation Report for NM_001035.3(RYR2):c.8209-3A>G]

NM_001035.3(RYR2):c.8209-3A>G

Gene:
RYR2:ryanodine receptor 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q43
Genomic location:
Preferred name:
NM_001035.3(RYR2):c.8209-3A>G
HGVS:
  • NC_000001.11:g.237659982A>G
  • NG_008799.2:g.622581A>G
  • NG_008799.3:g.622799A>G
  • NM_001035.3:c.8209-3A>GMANE SELECT
  • LRG_402t1:c.8209-3A>G
  • LRG_402:g.622799A>G
  • NC_000001.10:g.237823282A>G
  • NM_001035.2:c.8209-3A>G
  • c.8209-3A>G
Links:
dbSNP: rs376788358
NCBI 1000 Genomes Browser:
rs376788358
Molecular consequence:
  • NM_001035.3:c.8209-3A>G - intron variant - [Sequence Ontology: SO:0001627]
Observations:
1

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000060450Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely benign
(Sep 24, 2019)
germlineclinical testing

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

SCV000235153GeneDxcriteria provided, single submitter
Uncertain significance
(Mar 9, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown11not providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000060450.7

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

Description

The c.8209-3G>A variant in RYR2 is classified as likely benign because it has been identified in 0.15% (34/21760) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is located in the 3' splice region. Although a subset of computational tools predict a possible splicing impact, this information is not predictive enough to support pathogenicity in the absence of additional data. ACMG/AMP Criteria applied: BA1, PP3.

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

From GeneDx, SCV000235153.11

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

Description

The c.8209-3 A>G variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. In silico splice prediction algorithms demonstrate that c.8209-3 A>G may result in loss of the natural splice acceptor site of intron 54, which may cause abnormal gene splicing. This may lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. However, the majority of disease causing mutations in the RYR2 gene are missense changes. The NHLBI ESP Exome Variant Server reports c.8209-3 A>G was observed at a low frequency (4/3596) of alleles from individuals of African American background. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY,POSTMORTEM panel(s).

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

Last Updated: Jul 7, 2021

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