rs397516548

chr1-237640898-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2 BP4

The NM_001035.3(RYR2):c.7117G>T(p.Asp2373Tyr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000411 in 1,459,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 1/1 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: 0.0000041 (0 hom.)
• Consequence: RYR2 NM_001035.3 missense, splice_region
• Scores: Splicing: ADA: 0.002009
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 6.71

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 Uncertain_significance. Variant got 0 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RYR2
• BP4: Computational evidence support a benign effect (MetaRNN=0.33555442).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR2	NM_001035.3	c.7117G>T	p.Asp2373Tyr	missense_variant, splice_region_variant	47/105	ENST00000366574.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR2	ENST00000366574.7	c.7117G>T	p.Asp2373Tyr	missense_variant, splice_region_variant	47/105	1	NM_001035.3	P1
RYR2	ENST00000660292.2	c.7117G>T	p.Asp2373Tyr	missense_variant, splice_region_variant	47/106
RYR2	ENST00000659194.3	c.7117G>T	p.Asp2373Tyr	missense_variant, splice_region_variant	47/105
RYR2	ENST00000609119.2	c.7117G>T	p.Asp2373Tyr	missense_variant, splice_region_variant, NMD_transcript_variant	47/104	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000811 AC: 2 AN: 246646 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133578

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: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459674 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 725856

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000494 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 19, 2012

The Asp2373Tyr variant in RYR2 has not been reported in the literature nor previ ously identified by our laboratory. Computational analyses (biochemical amino ac id properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide stro ng support for or against an impact to the protein. Additional information is ne eded to fully assess the clinical signficance of this variant. -

Catecholaminergic polymorphic ventricular tachycardia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Jan 11, 2024

This missense variant replaces aspartic acid with tyrosine at codon 2373 of the RYR2 protein. Computational prediction tool 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/246646 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

Nov 28, 2022

This missense variant replaces aspartic acid with tyrosine at codon 2373 of 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 not been reported in individuals affected with RYR2-related disorders in the literature. This variant has been identified in 2/246646 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. -

Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 04, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 2373 of the RYR2 protein (p.Asp2373Tyr). This variant is present in population databases (rs397516548, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 43822). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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

Jan 21, 2022

The c.7117G>T (p.D2373Y) alteration is located in exon 47 (coding exon 47) of the RYR2 gene. This alteration results from a G to T substitution at nucleotide position 7117, causing the aspartic acid (D) at amino acid position 2373 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Benign	22
Dann	Benign	0.57
DEOGEN2	Uncertain	0.42	T;T
Eigen	Benign	-0.069
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.3	N;.
REVEL	Uncertain	0.51
Sift	Benign	0.24	T;.
Polyphen		0.020	B;.
Vest4		0.45
MutPred		0.28		Gain of phosphorylation at D2373 (P = 0.0065);.;
MVP		0.90
MPC		0.44
ClinPred		0.15	T
GERP RS		5.8
Varity_R		0.21
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0020
SpliceAI score (max)		0.030		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: rs397516548; hg19: chr1-237804198;