19-38499177-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP2 PP3_Moderate

The NM_000540.3(RYR1):c.6961A>T(p.Ile2321Phe) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2321V) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RYR1 NM_000540.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.18

Genes affected

RYR1 (HGNC:10483): (ryanodine receptor 1) This gene encodes a ryanodine receptor found in skeletal muscle. The encoded protein functions as a calcium release channel in the sarcoplasmic reticulum but also serves to connect the sarcoplasmic reticulum and transverse tubule. Mutations in this gene are associated with malignant hyperthermia susceptibility, central core disease, and minicore myopathy with external ophthalmoplegia. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-38499177-A-G is described in Lovd as [Pathogenic].
• PP2: Missense variant where missense usually causes diseases, RYR1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RYR1	NM_000540.3	c.6961A>T	p.Ile2321Phe	missense_variant	43/106	ENST00000359596.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RYR1	ENST00000359596.8	c.6961A>T	p.Ile2321Phe	missense_variant	43/106	5	NM_000540.3	A2
RYR1	ENST00000355481.8	c.6961A>T	p.Ile2321Phe	missense_variant	43/105	1		P4
RYR1	ENST00000594335.5	c.415A>T	p.Ile139Phe	missense_variant, NMD_transcript_variant	4/49	1
RYR1	ENST00000599547.6	c.6961A>T	p.Ile2321Phe	missense_variant, NMD_transcript_variant	43/80	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

RYR1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 19, 2021

This variant has not been reported in the literature in individuals affected with RYR1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with phenylalanine at codon 2321 of the RYR1 protein (p.Ile2321Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
Cadd	Benign	22
Dann	Benign	0.90
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.77
MutPred		0.61		Loss of ubiquitination at K2316 (P = 0.1139);Loss of ubiquitination at K2316 (P = 0.1139);
MVP		0.99
MPC		0.58
ClinPred		0.95	D
GERP RS		4.1
Varity_R		0.63
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-38989817;