rs727504630

Positions:

• chr1-237831507-TC-AT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001035.3(RYR2):​c.14757-7_14757-6delinsAT variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RYR2 NM_001035.3 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 0.256

Genes affected

RYR2 (HGNC:10484): (ryanodine receptor 2) This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-237831507-TC-AT is Benign according to our data. Variant chr1-237831507-TC-AT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179105.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.14757-7_14757-6delinsAT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.14757-7_14757-6delinsAT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001035.3	ENSP00000355533	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 30, 2017	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 11, 2013	The 14757-7_14757-6delinsAT variant in RYR2 has been reported in 3 individuals w ith CPVT or sudden death (Tan 2005, Hofman 2010, van der Werf 2012), though 1 in dividual carried other variants of unknown significance and in another family, a t least 4 relatives carried the variant and were unaffected (ages not specified) . This variant is located in the 3' splice region. Computational tools do not su ggest an impact to splicing, though this information is not predictive enough to determine pathogenicity. While the presence of this variant in multiple affecte d individuals suggests that it may play a role in disease, the presence in multi ple unaffected relatives brings into question its ability to cause disease in is olation. In summary, additional information is needed to fully assess the clinic al significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 20, 2020	Variant summary: RYR2 c.14757-7_14757-6delinsAT alters two nucleotides located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant has also been reported in the literature as c.14757-6C>T; c.14757-7T>A . Although the combined variant c.14757-7_14757-6delinsA is not reported in population databases, it appears that most reads in gnomAD with c.14757-6C>T also carry c.14757-7T>A . Thus, it can be estimated that the combined allele c.14757-7_14757-6delinsA was found at a frequency of approximately 0.00021 in 275638 control chromosomes, predominantly at a frequency of 0.00042 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 16.8- fold the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.14757-7_14757-6delinsAT has been reported in the literature in at least 3 probands with catecholaminergic polymorphic ventricular tachycardia (CPVT) and/or sudden death, without strong evidence for causality (examples- Tan_2005, Hofman_2010, vanderWerf_2012). The variant was also found in unaffected family members (example-Hofman_2010), and segregation with disease was not clear. These reports do 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 other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as likely benign, and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

Cardiomyopathy Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 26, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 20, 2021	- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs727504630; hg19: chr1-237994807;