rs727503401

chr1-237639069-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5 PP2 PP3_Strong

The NM_001035.3(RYR2):c.6983C>T(p.Pro2328Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P2328S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4
• Conservation: PhyloP100: 7.80

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-237639068-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 840374.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, RYR2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.6983C>T	p.Pro2328Leu	missense_variant	46/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.6983C>T	p.Pro2328Leu	missense_variant	46/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.6983C>T	p.Pro2328Leu	missense_variant	46/106
RYR2	ENST00000659194.3	c.6983C>T	p.Pro2328Leu	missense_variant	46/105
RYR2	ENST00000609119.2	c.6983C>T	p.Pro2328Leu	missense_variant, NMD_transcript_variant	46/104	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249156 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135180

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461648 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727108

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 04, 2020	Variant summary: RYR2 c.6983C>T (p.Pro2328Leu) results in a non-conservative amino acid change located in the RIH Domain (IPR000699) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249156 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6983C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. However, another variant resulting in a different amino acid substitution at the same position (c.6982C>T, p.P2328S) has been reported in the literature in individuals affected with tachycardia (e.g. PMID: 15197150). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 20, 2013	Variant classified as Uncertain Significance - Favor Pathogenic. The Pro2328Leu variant in RYR2 has not been reported in individuals with cardiomyopathy or in l arge population studies. However, another variant at this position, Pro2328Ser, is strongly associated with CPVT, and segregated with disease in >10 individuals in one family (Laitinen 2001, Lehnart 2004), suggesting that a change at this p osition would not be tolerated. In addition, computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest th at the Pro2328Leu variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Although this data supports that the Pro2328Leu variant may be pathogenic, additional studies are needed to fully assess its clinical significance. -

Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 09, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro2328 amino acid residue in RYR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15197150; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function. ClinVar contains an entry for this variant (Variation ID: 165105). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. This variant is present in population databases (rs727503401, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2328 of the RYR2 protein (p.Pro2328Leu). -

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 missense variant replaces proline with leucine at codon 2328 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the cytoplasmic domain. Rare nontruncating variants in this region (a.a. 2138-2538) have been shown to be significantly overrepresented in individuals with catecholaminergic polymorphic ventricular tachycardia (PMID: 19926015, 30696458). This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 1/249156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Pro2328Ser (Clinvar variation ID: 12960), is known to cause familial polymorphic ventricular tachycardia, suggesting that proline at this position is important for RYR2 protein function. Although there is a suspicion for a pathogenic role, 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

May 19, 2023

This missense variant replaces proline with leucine at codon 2328 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region of the cytoplasmic domain. Rare nontruncating variants in this region (a.a. 2138-2538) have been shown to be significantly overrepresented in individuals with catecholaminergic polymorphic ventricular tachycardia (PMID: 19926015, 30696458). This variant has not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 1/249156 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Pro2328Ser (Clinvar variation ID: 12960), is known to cause familial polymorphic ventricular tachycardia, suggesting that proline at this position is important for RYR2 protein function. Although there is a suspicion for a pathogenic role, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-9.2	D;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.93
MutPred		0.82		Gain of MoRF binding (P = 0.0519);.;
MVP		0.80
MPC		1.2
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.80
gMVP		0.91

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: rs727503401; hg19: chr1-237802369; COSMIC: COSV63717480;