chr15-33660232-T-G

Position:

• chr15-33660232-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001036.6(RYR3):​c.4431T>G​(p.Ser1477Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000515 in 1,552,544 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RYR3 NM_001036.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.261

Genes affected

RYR3 (HGNC:10485): (ryanodine receptor 3) The protein encoded by this gene is a ryanodine receptor, which functions to release calcium from intracellular storage for use in many cellular processes. For example, the encoded protein is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum followed by depolarization of T-tubules. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

RYR3 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR3	NM_001036.6	c.4431T>G	p.Ser1477Arg	missense_variant	34/104	ENST00000634891.2	NP_001027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RYR3	ENST00000634891.2	c.4431T>G	p.Ser1477Arg	missense_variant	34/104	1	NM_001036.6	ENSP00000489262.1

Frequencies

GnomAD3 genomes AF: 0.0000396 AC: 6 AN: 151702 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.000479

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1400842 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 691036

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: 0.00

Gnomad4 OTH exome AF: 0.0000344

GnomAD4 genome AF: 0.0000396 AC: 6 AN: 151702 Hom.: 0 Cov.: 33 AF XY: 0.0000405 AC XY: 3 AN XY: 74094

Gnomad4 AFR AF: 0.0000727

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000831

ESP6500AA AF: 0.000237 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2023

The c.4431T>G (p.S1477R) alteration is located in exon 34 (coding exon 34) of the RYR3 gene. This alteration results from a T to G substitution at nucleotide position 4431, causing the serine (S) at amino acid position 1477 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Epileptic encephalopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1477 of the RYR3 protein (p.Ser1477Arg). This variant is present in population databases (rs377360254, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RYR3-related conditions. ClinVar contains an entry for this variant (Variation ID: 530984). 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 RYR3 protein function with a positive predictive value of 80%. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;.;.;.
Eigen	Benign	0.025
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.4	M;M;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.1	.;D;D;.;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0080	.;D;D;.;.
Polyphen		0.64	P;D;.;.;.
Vest4		0.97
MutPred		0.21		Loss of ubiquitination at K1480 (P = 0.0343);Loss of ubiquitination at K1480 (P = 0.0343);Loss of ubiquitination at K1480 (P = 0.0343);Loss of ubiquitination at K1480 (P = 0.0343);Loss of ubiquitination at K1480 (P = 0.0343);
MVP		0.96
MPC		0.55
ClinPred		0.99	D
GERP RS		1.2
Varity_R		0.62
gMVP		0.92

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: rs377360254; hg19: chr15-33952433;