NM_001035.3(RYR2):c.12492G>A (p.Gln4164=) AND not specified

Germline classification:: Benign (2 submissions)
Last evaluated:: Sep 10, 2018
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:: RCV000182645.10

Allele description [Variation Report for NM_001035.3(RYR2):c.12492G>A (p.Gln4164=)]

NM_001035.3(RYR2):c.12492G>A (p.Gln4164=)

Genes:

LOC126806068:BRD4-independent group 4 enhancer GRCh37_chr1:237947411-237948610 [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.12492G>A (p.Gln4164=)

Other names:

p.Q4164Q:CAG>CAA

HGVS:

NC_000001.11:g.237784204G>A
NG_008799.3:g.747021G>A
NM_001035.3:c.12492G>AMANE SELECT
NP_001026.2:p.Gln4164=
LRG_402t1:c.12492G>A
LRG_402:g.747021G>A
LRG_402p1:p.Gln4164=
NC_000001.10:g.237947504G>A
NG_008799.2:g.746803G>A
NM_001035.2:c.12492G>A

Links:

dbSNP: rs377293019

NCBI 1000 Genomes Browser:

rs377293019

Molecular consequence:

NM_001035.3:c.12492G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000235020	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Benign (Oct 3, 2014)	germline	clinical testing	Citation Link,
SCV000920168	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Sep 10, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000235020

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Benign
(Oct 3, 2014)

germline

clinical testing

Citation Link,

SCV000920168

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Benign
(Sep 10, 2018)

germline

clinical testing

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

Citation Link

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

Citations

PubMed

Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers.

Berge KE, Haugaa KH, Früh A, Anfinsen OG, Gjesdal K, Siem G, Oyen N, Greve G, Carlsson A, Rognum TO, Hallerud M, Kongsgård E, Amlie JP, Leren TP.

Scand J Clin Lab Invest. 2008;68(5):362-8. doi: 10.1080/00365510701765643.

PubMed [citation]

PMID:: 18752142

Details of each submission

From GeneDx, SCV000235020.10

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000920168.1

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

Description

Variant summary: RYR2 c.12492G>A alters a conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0002 in 276742 control chromosomes (gnomAD). The observed variant frequency is approximately 8-fold above the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. The variant, c.12492G>A, has been reported in the literature in one individual affected with Cardiomyopathy as a benign variant (Berge_2008). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.

#	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 20, 2024

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