rs200236750

chr1-237566672-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2 BP4_Moderate BP6 BS1 BS2

The NM_001035.3(RYR2):c.3320C>T(p.Thr1107Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,613,804 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1107T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (1 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:10
• Conservation: PhyloP100: 1.90

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 Benign. Variant got -10 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.09495711).
• BP6: Variant 1-237566672-C-T is Benign according to our data. Variant chr1-237566672-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43768.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Uncertain_significance=1}. Variant chr1-237566672-C-T is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000526 (80/152118) while in subpopulation NFE AF= 0.00097 (66/68024). AF 95% confidence interval is 0.000782. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.3320C>T	p.Thr1107Met	missense_variant	28/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.3320C>T	p.Thr1107Met	missense_variant	28/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.3320C>T	p.Thr1107Met	missense_variant	28/106
RYR2	ENST00000659194.3	c.3320C>T	p.Thr1107Met	missense_variant	28/105
RYR2	ENST00000609119.2	c.3320C>T	p.Thr1107Met	missense_variant, NMD_transcript_variant	28/104	5

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000421 AC: 105 AN: 249172 Hom.: 0 AF XY: 0.000436 AC XY: 59 AN XY: 135178

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.000850

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000593

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000815 AC: 1192 AN: 1461686 Hom.: 1 Cov.: 31 AF XY: 0.000773 AC XY: 562 AN XY: 727130

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000893

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000925

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.000526 AC: 80 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74310

Gnomad4 AFR AF: 0.000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000970

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000530 Hom.: 0

Bravo AF: 0.000540

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000600 AC: 5

ExAC AF: 0.000322 AC: 39

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RYR2: BP4 -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Feb 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	This variant is associated with the following publications: (PMID: 23861362, 27538377, 27435932, 22374134, 19926015, 24025405, 20157052, 22677073, 26573135, 25370123, 28404607, 28567303, 30403697, 29396286) -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 21, 2022	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 25, 2019	Variant classified as Uncertain Significance - Favor Benign. The p.Thr1107Met variant in RYR2 has been reported in an individual with CVPT, a case of SIDS, a Japanese family with HCM, an individual with DCM, and as a secondary finding in an individual with oculocutaneous albinism without mention of cardiac phenotype (Medeiros-Domingo et al 2009, Methner et al. 2016, Stavropolous et al. 2017, Noboru et al. 2006 (abstract only), LMM data). It has been reported in ClinVar (Variation ID #43768). In vitro functional studies provide some evidence that the p.Thr1107Met variant may impact protein function (Tang et al. 2012). However, these types of assays may not accurately represent biological function. This variant has been identified in 79/126600 of European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs200236750). Threonine (Thr) at position 1107 is not conserved in mammals or evolutionarily distant species, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, due to conflicting data, the clinical significance of the p.Thr1107Met variant is uncertain. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 07, 2021	Variant summary: RYR2 c.3320C>T (p.Thr1107Met) results in a non-conservative amino acid change located in the Ryanodine receptor, SPRY domain 2 & B30.2/SPRY domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 249172 control chromosomes, predominantly at a frequency of 0.00085 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 14 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3320C>T has been reported in the literature in individuals affected with Arrhythmia and other cardiopathologies (example: Fujino_2006, Tester_2012, Medeiros-Domingo_2009, Ghazani_2017, Landstrom_2017, Methner_2016, Rangaraju_2018, Roston_2018, Stavropoulos_2016). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. Co-occurrences with other pathogenic variants have been reported (KCNH2 c.2398+5G>T; CASQ2 IVS5+1G>C (c.606+1G>C); MYH7 c.1447G>A/p.E483K) (Roston_2018, Tester_2012, Internal database), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (example: Tang_2012). The most pronounced variant effect results in >50%-90% of normal activity. Seven ClinVar submitters have assessed this variant since 2014: three report the variant as likely benign, three as of uncertain significance, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign. -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Death in infancy Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Forensic Genetics Laboratory, Harris County Institute of Forensic Sciences

Mar 27, 2015

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 05, 2019

- -

RYR2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 10, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.095	T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.11	N;.
MutationTaster	Benign	0.69	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.54	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D;T
Polyphen		0.58	P;.
Vest4		0.78
MVP		0.70
MPC		0.50
ClinPred		0.016	T
GERP RS		5.4
Varity_R		0.094
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs200236750; hg19: chr1-237729972; COSMIC: COSV63660552;