1-237595526-T-C

Position:

• chr1-237595526-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001035.3(RYR2):​c.4465T>C​(p.Cys1489Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,612,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. C1489C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:9 B:2
• Conservation: PhyloP100: 8.01

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23909247).
• BP6: Variant 1-237595526-T-C is Benign according to our data. Variant chr1-237595526-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178120.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=9}.
• BS2: High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR2	NM_001035.3	c.4465T>C	p.Cys1489Arg	missense_variant	34/105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.4465T>C	p.Cys1489Arg	missense_variant	34/105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000609119.2	n.4465T>C		non_coding_transcript_exon_variant	34/104	5		ENSP00000499659.2
RYR2	ENST00000660292.2	c.4465T>C	p.Cys1489Arg	missense_variant	34/106			ENSP00000499787.2
RYR2	ENST00000659194.3	c.4465T>C	p.Cys1489Arg	missense_variant	34/105			ENSP00000499653.3

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000157 AC: 39 AN: 247670 Hom.: 0 AF XY: 0.000164 AC XY: 22 AN XY: 134360

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000442

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000169

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.000175 AC: 255 AN: 1460382 Hom.: 0 Cov.: 31 AF XY: 0.000190 AC XY: 138 AN XY: 726402

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000495

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000203

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74352

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000103 Hom.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:9 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2020	The RYR2 c.4465T>C; p.Cys1489Arg variant (rs200450676) is reported in the literature in an individual affected with hypertrophic cardiomyopathy and another individual with sudden unexpected death in epilepsy (Bagnall 2016, Lopes 2015). This variant is found in the Latino population with an overall allele frequency of 0.04% (15/34756 alleles) in the Genome Aggregation Database. The cysteine at codon 1489 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Cys1489Arg variant is uncertain at this time. References: Bagnall et al., Exome-based analysis of cardiac arrhythmia, respiratory control, and epilepsy genes in sudden unexpected death in epilepsy. Ann Neurol. 2016 Apr;79(4):522-34. Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2024	Reported in individuals with HCM, sudden unexplained death (SUD), arrhythmogenic cardiomyopathy and sudden unexplained death in epilepsy (SUDEP) in published literature (PMID: 26704558, 25351510, 35819174, 27930701); Also identified in a cohort of individuals undergoing clinical exome sequencing (PMID: 28404607); although, the indication for testing, follow-up cardiac evaluations and segregation studies were not reported; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (PMID: 19926015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27482086, 26704558, 27930701, 35819174, 25351510, 19926015, 28404607, 32152366) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2015	- -

Cardiomyopathy Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jul 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 27, 2020	- -

Long QT syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Apr 12, 2017

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 25, 2019

The p.Cys1489Arg variant in RYR2 has now been identified by our laboratory in 1 Black individual and 1 Caucasian individual with DCM (LMM unpublished data). In addition, it has also been identified in 1/8376 European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs200450676). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is needed to fully assess the clinical significance of this variant. -

Catecholaminergic polymorphic ventricular tachycardia 1;C1832931:Arrhythmogenic right ventricular dysplasia 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2024

The p.C1489R variant (also known as c.4465T>C), located in coding exon 34 of the RYR2 gene, results from a T to C substitution at nucleotide position 4465. The cysteine at codon 1489 is replaced by arginine, an amino acid with highly dissimilar properties. This variant has been identified in a hypertrophic cardiomyopathy cohort, in an individual from a sudden unexplained death in epilepsy cohort with history of nocturnal seizures, and in an exome sequencing cohort; however clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301; Bagnall RD et al. Ann. Neurol., 2016 Apr;79:522-34). This alteration has also been seen in a sudden unexplained death cohort with variants in other cardiac-related genes (Sanchez O et al. PLoS One, 2016 Dec;11:e0167358). This variant has also been reported in an arrhythmogenic right ventricular cardiomyopathy (ARVC) cohort (Goudal A et al. Hum Mutat, 2022 Sep;43:1333-1342). This amino acid position is not well 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. -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Uncertain	0.52	D;T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.9	D;.
REVEL	Uncertain	0.38
Sift	Benign	0.87	T;.
Polyphen		0.53	P;.
Vest4		0.97
MVP		0.42
MPC		0.66
ClinPred		0.099	T
GERP RS		5.5
Varity_R		0.76
gMVP		0.80

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: rs200450676; hg19: chr1-237758826;