rs769219555

Variant names:

• chr1-237648612-C-T
• rs769219555
• NM_001035.3:c.7511C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP2 PP3 BS1_Supporting BS2

The NM_001035.3(RYR2):​c.7511C>T​(p.Thr2504Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000355 in 1,607,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2504A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense, splice_region
• Scores: Splicing: ADA: 0.9968
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.85
• Publications: 22 publications found

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]

RYR2 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 2

  Inheritance: AD Classification: DEFINITIVE, NO_KNOWN Submitted by: Laboratory for Molecular Medicine, Ambry Genetics
• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• catecholaminergic polymorphic ventricular tachycardia 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• arrhythmogenic right ventricular cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP2: Missense variant in the RYR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 195 curated pathogenic missense variants (we use a threshold of 10). The gene has 55 curated benign missense variants. Gene score misZ: 5.7809 (above the threshold of 3.09). Trascript score misZ: 6.4158 (above the threshold of 3.09). GenCC associations: The gene is linked to hypertrophic cardiomyopathy, catecholaminergic polymorphic ventricular tachycardia 1, catecholaminergic polymorphic ventricular tachycardia, arrhythmogenic right ventricular dysplasia 2, arrhythmogenic right ventricular cardiomyopathy.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000789 (12/152156) while in subpopulation AFR AF = 0.000193 (8/41436). AF 95% confidence interval is 0.0000957. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.7511C>T	p.Thr2504Met	missense_variant, splice_region_variant	Exon 49 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.7511C>T	p.Thr2504Met	missense_variant, splice_region_variant	Exon 49 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.7511C>T	p.Thr2504Met	missense_variant, splice_region_variant	Exon 49 of 106			ENSP00000499393.2
RYR2	ENST00000609119.2	n.7511C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 49 of 104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152156 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000420 AC: 10 AN: 237960 AF XY: 0.0000466

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 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

African (AFR) AF: 0.0000598 AC: 2 AN: 33418

American (AMR) AF: 0.0000227 AC: 1 AN: 44034

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39638

South Asian (SAS) AF: 0.0000825 AC: 7 AN: 84822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53076

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5728

European-Non Finnish (NFE) AF: 0.0000280 AC: 31 AN: 1108522

Other (OTH) AF: 0.0000333 AC: 2 AN: 60142

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74332

African (AFR) AF: 0.000193 AC: 8 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000662 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Jun 23, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RYR2 c.7511C>T (p.Thr2504Met) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. 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, predominantly at a frequency of 0.00021 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7511C>T has been reported in a variety of cardiac conditions, such as, in affected family members from a single family affected with arrhythmogenic right ventricular cardiomyopathy type 2 (ARVD2) (Tiso_2001), in affected and unaffected family members of a family affected with ventricular tachycardias (Bauce_2002), an individual with idopathic ventricular tachycardia (IVT) (Akilzhanova_2014) and 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). 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). The following publications have been ascertained in the context of this evaluation (PMID: 24978818, 12106942, 28416588, 33552729, 32152366, 15364613, 11159936). ClinVar contains an entry for this variant (Variation ID: 567443). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Apr 30, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 individuals affected with idiopathic ventricular tachycardia (PMID: 24978818, 33552729), dilated cardiomyopathy (PMID: 28416588), and primary cardiomyopathy (PMID: 37477868). 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

Nov 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). 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 missense change has been observed in individual(s) with clinical features of RYR2-related conditions (PMID: 11159936, 12106942, 24978818, 28416588, 32152366, 37227348). ClinVar contains an entry for this variant (Variation ID: 567443). 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. Experimental studies have shown that this missense change affects RYR2 function (PMID: 15364613). 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. -

Cardiovascular phenotype Uncertain:1

Jun 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 also been seen in individuals with ventricular tachycardia, and this variant 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; Olubando D et al. J Hum Genet, 2020 Jun;65:531-539). 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. Based on the available evidence, the clinical significance of this variant remains unclear. -

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;.
PhyloP100		7.9
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
Mutation Taster		=21/79	disease causing

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

Other links and lift over

dbSNP: rs769219555; hg19: chr1-237811912;