chr1-237377365-G-T

Variant names:

• chr1-237377365-G-T
• rs397516539
• NM_001035.3:c.506G>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001035.3(RYR2):​c.506G>T​(p.Arg169Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R169Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0
• Publications: 10 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: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001035.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237377365-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 43801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 1-237377365-G-T is Pathogenic according to our data. Variant chr1-237377365-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR2	NM_001035.3	c.506G>T	p.Arg169Leu	missense_variant	Exon 8 of 105	ENST00000366574.7	NP_001026.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR2	ENST00000366574.7	c.506G>T	p.Arg169Leu	missense_variant	Exon 8 of 105	1	NM_001035.3	ENSP00000355533.2
RYR2	ENST00000661330.2	c.506G>T	p.Arg169Leu	missense_variant	Exon 8 of 106			ENSP00000499393.2
RYR2	ENST00000609119.2	n.506G>T		non_coding_transcript_exon_variant	Exon 8 of 104	5		ENSP00000499659.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Mar 16, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

While the R169L variant in the RYR2 gene has not been reported to our knowledge, a pathogenic variant affectingthis same residue, R169Q, has been reported in association with exercised induced ventricular tachycardiaand was absent in 100 reference alleles (Hsueh C et al., 2006). Additionally, variants in nearby residues(P164S, A165D, R176Q) have been reported in HGMD in association with polymorphic ventriculartachycardia and arrhythmogenic right ventricular dysplasia type 2 (Stenson P et al., 2014). Furthermore,R169L is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenicmissense variants occur (Medeiros-Domingo et al., 2009). R169L results in a non-conservative amino acid substitution at a position that is conserved across species. In silico analysis predicts is damaging to theprotein structure/function. Finally, the R169L variant was not observed in approximately 6100 individualsof European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is nota common benign variant in these populations. In summary, R169L in the RYR2 gene is interpreted as a pathogenic variant.

Cardiovascular phenotype Pathogenic:1

Mar 04, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R169L variant (also known as c.506G>T), located in coding exon 8 of the RYR2 gene, results from a G to T substitution at nucleotide position 506. The arginine at codon 169 is replaced by leucine, an amino acid with dissimilar properties. This variant was reported as de novo in one individual with a history of syncope, who was part of a catecholaminergic polymorphic ventricular tachycardia (CPVT) testing cohort (Ohno S et al. PLoS ONE, 2015 Jun;10:e0131517). An alternate amino acid substitution at this position, p.R169Q, has also been reported in CPVT cohorts, including two apparently de novo cases (Hsueh CH et al. Int J Cardiol. 2006;108:276-8; Ohno S et al. PLoS ONE, 2015 Jun;10:e0131517). 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 majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;.
PhyloP100		10
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.3	D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	.;.
Vest4		0.97
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.90
gMVP		0.89
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397516539; hg19: chr1-237540665;