rs748307254

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_001035.3(RYR2):c.5717T>C(p.Met1906Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,458,418 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

RYR2
NM_001035.3 missense, splice_region

Scores

Splicing: ADA: 0.4339

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 8.02

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP2

Missense variant where missense usually causes diseases, RYR2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3 linkuse as main transcript	c.5717T>C	p.Met1906Thr	missense_variant, splice_region_variant	38/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7 linkuse as main transcript	c.5717T>C	p.Met1906Thr	missense_variant, splice_region_variant	38/105	1	NM_001035.3	P1	Q92736-1
RYR2	ENST00000660292.2 linkuse as main transcript	c.5717T>C	p.Met1906Thr	missense_variant, splice_region_variant	38/106
RYR2	ENST00000659194.3 linkuse as main transcript	c.5717T>C	p.Met1906Thr	missense_variant, splice_region_variant	38/105
RYR2	ENST00000609119.2 linkuse as main transcript	c.5717T>C	p.Met1906Thr	missense_variant, splice_region_variant, NMD_transcript_variant	38/104	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000123

AC:

AN:

243350

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

131914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000170

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1458418

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

725154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000429

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000248

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

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

Aug 08, 2023

This variant is located in the RYR2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with catecholaminergic polymorphic ventricular tachycardia with prolonged QT interval, who also carried another pathogenic variant in the RYR2 gene (PMID: 29951146). This variant has been identified in 3/243350 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

Jul 25, 2023

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2012

p.Met1906Thr (ATG>ACG): c.5717 T>C in exon 38 of the RYR2 gene (NM_001035.2). The Met1906Thr variant in the RYR2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Met1906Thr results in a non-conservative amino acid substitution of a non-polar Methionine residue with a polar Threonine residue at a position that is conserved across species. In silico analysis predicts Met1906Thr is probably damaging to the protein structure/function. Also, the NHLBI ESP Exome Variant Server reports Met1906Thr was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Nevertheless, no mutations in nearby codons have been reported in association with ARVC or an RYR2-related phenotype, indicating this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if Met1906Thr is a disease-causing mutation or a rare benign variant. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is primarily an autosomal dominant disease characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death (McNally E et al., 2009; Nava A et al., 2000). ARVC is most frequently caused by mutations in the genes encoding desmosomal proteins, complexes that maintain cell-to-cell connections and provide mechanical attachments among adjacent cells. Less commonly, ARVC may be caused by mutations in genes that encode proteins that maintain calcium homeostasis (McNally E et al., 2009). Approximately 50% of patients with autosomal dominant CPVT have been reported to have a mutation in the RYR2 gene, while mutations in the RYR2 gene associated with ARVC are rare (McNally E et al., 2009; Napolitano C et al., 2012). The variant is found in ARVC panel(s). -

Catecholaminergic polymorphic ventricular tachycardia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 22, 2022

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1906 of the RYR2 protein (p.Met1906Thr). This variant is present in population databases (rs748307254, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 29951146). ClinVar contains an entry for this variant (Variation ID: 201257). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2023

The p.M1906T variant (also known as c.5717T>C), located in coding exon 38 of the RYR2 gene, results from a T to C substitution at nucleotide position 5717. The methionine at codon 1906 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a case report of an individual who experienced sudden cardiac arrest at a young age; however, an additional alteration in RYR2 was identified (Saito A et al. J Arrhythm, 2018 Jun;34:291-293). Additionally, this alteration has been reported in a hypertrophy cardiomyopathy cohort (Chung H et al. J Cardiovasc Magn Reson, 2021 Mar;23:18). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Uncertain

-0.040

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

D;D

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Uncertain

-0.045

MutationAssessor

Uncertain

2.5

M;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-4.3

D;.

REVEL

Uncertain

0.58

Sift

Uncertain

0.0010

D;.

Polyphen

1.0

D;.

Vest4

0.92

MutPred

0.34

Loss of catalytic residue at V1902 (P = 0.0325);.;

MVP

0.53

MPC

1.1

ClinPred

0.96

GERP RS

5.4

Varity_R

0.72

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.43

dbscSNV1_RF

Benign

0.37

SpliceAI score (max)

0.020

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.

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