Variant rs769219555 details in Genebe, Genetics Data Aggregator

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR2. . Gene score misZ 5.7809 (greater than the threshold 3.09). Trascript score misZ 6.4158 (greater than threshold 3.09). GenCC has associacion of gene with hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 2, catecholaminergic polymorphic ventricular tachycardia.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.7511C>T	p.Thr2504Met	missense_variant, splice_region_variant	49/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.7511C>T	p.Thr2504Met	missense_variant, splice_region_variant	49/105	1	NM_001035.3	P1	Q92736-1
RYR2	ENST00000660292.2 linkuse as main transcript	c.7511C>T	p.Thr2504Met	missense_variant, splice_region_variant	49/106
RYR2	ENST00000659194.3 linkuse as main transcript	c.7511C>T	p.Thr2504Met	missense_variant, splice_region_variant	49/105
RYR2	ENST00000609119.2 linkuse as main transcript	c.7511C>T	p.Thr2504Met	missense_variant, splice_region_variant, NMD_transcript_variant	49/104	5

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

12

AN:

152156

Hom.:

0

Cov.:

33

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000420

AC:

10

AN:

237960

Hom.:

0

AF XY:

0.0000466

AC XY:

6

AN XY:

128732

show subpopulations

Gnomad AFR exome

AF:

0.000207

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000694

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000374

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

AF:

0.0000309

AC:

45

AN:

1455282

Hom.:

0

Cov.:

30

AF XY:

0.0000332

AC XY:

24

AN XY:

723146

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000825

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000280

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000789

AC:

12

AN:

152156

Hom.:

0

Cov.:

33

AF XY:

0.0000404

AC XY:

3

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000153

Hom.:

0

Bravo

AF:

0.000110

ExAC

AF:

0.0000662

AC:

8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 20, 2023

This missense variant replaces threonine with methionine at codon 2504 of the RYR2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant changes calcium channel activities (PMID: 15364613). This variant has been reported in a family affected with arrhythmogenic right ventricular dysplasia type 2 including three affected individuals who also carried another pathogenic RYR2 variant (PMID: 11159936). This variant has also been reported in two related individuals affected with polymorphic ventricular arrhythmia (PMID: 12106942) as well as in three unaffected family members. Additionally, this variant has been reported in an individual affected with idiopathic ventricular tachycardia (PMID: 24978818) and in an individual affected with dilated cardiomyopathy (PMID: 28416588). This variant has been identified in 13/269360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 03, 2023

This missense variant replaces threonine with methionine at codon 2504 of the RYR2 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant changes calcium channel activities (PMID: 15364613). This variant has been reported in a family affected with arrhythmogenic right ventricular dysplasia type 2 including three affected individuals who also carried another pathogenic RYR2 variant (PMID: 11159936). This variant has also been reported in two related individuals affected with polymorphic ventricular arrhythmia (PMID: 12106942) as well as in three unaffected family members. Additionally, this variant has been reported in an individual affected with idiopathic ventricular tachycardia (PMID: 24978818) and in an individual affected with dilated cardiomyopathy (PMID: 28416588). This variant has been identified in 13/269360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 03, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects RYR2 function (PMID: 15364613). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 567443). This missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 11159936, 12106942, 24978818, 28416588). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 2504 of the RYR2 protein (p.Thr2504Met). -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2023

The p.T2504M variant (also known as c.7511C>T), located in coding exon 49 of the RYR2 gene, results from a C to T substitution at nucleotide position 7511. The threonine at codon 2504 is replaced by methionine, an amino acid with similar properties. This variant co-occurred with an RYR2 pathogenic variant in a family reported to have arrhythmogenic right ventricular cardiomyopathy (Bauce B et al. Am J Cardiol, 2000 Mar;85:573-9; Tiso N et al. Hum Mol Genet, 2001 Feb;10:189-94). This variant has been seen in an individual with idiopathic ventricular tachycardia, and was also seen in two individuals with arrhythmia from a family in which five unaffected relatives carried the variant (Bauce B et al. J Am Coll Cardiol, 2002 Jul;40:341-9; Akilzhanova A et al. PLoS One, 2014 Jun;9:e101059). This variant has also been detected in a dilated cardiomyopathy cohort and in a cohort with developmental disorders; however, details were limited (Dal Ferro M et al. Heart, 2017 11;103:1704-1710; Mcrae et al. Nature, 2017 02;542:433-438). This variant and the double mutant p.T2504M/p.R176Q have been reported to impact protein function in in vitro assays; however, the physiological relevance in the context of p.T2504M alone is unclear (Thomas NL. Cardiovasc Res. 2004 Oct;64(1):52-60). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 15, 2023

Variant summary: RYR2 c.7511C>T (p.Thr2504Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. As the variant alters the penultimate nucleotide of exon 49 located in the exonic splice region near the canonical intron 49 splice donor site, several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' splicing donor site, while one predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.2e-05 in 237960 control chromosomes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (3.4e-05), strongly suggesting that the variant is benign. c.7511C>T has been reported in the literature in a variety of cardiac conditions, such as, 1. co-occurring with a different pathogenic RYR2 variant (p.Arg176Gln) in affected family members from a single family affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2) (Tiso_2001), 2. in affected and unaffected family members of a family affected with ventricular tachycardias (Bauce_2002); 3. an individual with idopathic ventricular tachycardia (IVT) (Akilzhanova_2014) and 4. an individual with dilated cardiomyopathy (DCM) (Dal Ferro_2017). Since the penetrance due to this variant appears to be lower than expected, no conclusions can be drawn from these data. At-least one co-occurrence with another pathogenic variant has been reported (Tiso_2001, RYR2 c.527G>A, p.Arg176Gln), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect in isolation (Thomas_2004). At-least two recent studies have categorized this variant as "benign" (Olubando_2020, Guelly_2021). The following publications have been ascertained in the context of this evaluation (PMID: 24978818, 12106942, 28416588, 33552729, 32152366, 15364613, 11159936). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.51

D

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

33

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

D;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.76

D

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

1.0

D

PrimateAI

Pathogenic

0.83

D

PROVEAN

Pathogenic

-5.5

D;.

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0090

D;.

Polyphen

1.0

D;.

Vest4

0.81

MVP

0.98

MPC

1.2

ClinPred

0.81

D

GERP RS

4.7

Varity_R

0.35

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs769219555

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over