rs764262446

Positions:

chr19-38452824-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP2PP3_ModeratePP5

The NM_000540.3(RYR1):c.1250T>C(p.Leu417Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 1,439,116 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).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:2

Conservation

PhyloP100: 5.63

Variant links:

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]

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RYR1. . Gene score misZ 1.918 (greater than the threshold 3.09). Trascript score misZ 3.9788 (greater than threshold 3.09). GenCC has associacion of gene with King-Denborough syndrome, congenital multicore myopathy with external ophthalmoplegia, autosomal recessive centronuclear myopathy, RYR1-related myopathy, lethal multiple pterygium syndrome, malignant hyperthermia of anesthesia, benign Samaritan congenital myopathy, malignant hyperthermia, susceptibility to, 1, congenital myopathy with myasthenic-like onset, central core myopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.938

PP5

Variant 19-38452824-T-C is Pathogenic according to our data. Variant chr19-38452824-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 544398.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=3, Likely_pathogenic=3}. Variant chr19-38452824-T-C is described in Lovd as [Likely_pathogenic]. Variant chr19-38452824-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RYR1	NM_000540.3 linkuse as main transcript	c.1250T>C	p.Leu417Pro	missense_variant	13/106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
RYR1	ENST00000359596.8 linkuse as main transcript	c.1250T>C	p.Leu417Pro	missense_variant	13/106	5	NM_000540.3	ENSP00000352608.2	P21817-1
RYR1	ENST00000355481.8 linkuse as main transcript	c.1250T>C	p.Leu417Pro	missense_variant	13/105	1		ENSP00000347667.3	P21817-2
RYR1	ENST00000599547.6 linkuse as main transcript	n.1250T>C		non_coding_transcript_exon_variant	13/80	2		ENSP00000471601.2	M0R127

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000434

AC:

AN:

207268

Hom.:

AF XY:

0.0000355

AC XY:

AN XY:

112616

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000268

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:

0.0000112

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000132

AC:

AN:

1439116

Hom.:

Cov.:

AF XY:

0.00000980

AC XY:

AN XY:

714082

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000197

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:

0.00000999

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2024	Previously identified in patients tested at GeneDx and in the literature with RYR1-related myopathy who had a second RYR1 variant, however phase was not determined (PMID: 33642296); Previously reported in the heterozygous state in a patient with fetal akinesia and moderate myopathy (PMID: 35428369); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21911697, 33767344, 22473935, 33146414, 34008892, 33642296, 35428369, 37510394) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 05, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2020	- -

RYR1-related disorder

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 18, 2024	The RYR1 c.1250T>C variant is predicted to result in the amino acid substitution p.Leu417Pro. This variant was reported in the compound heterozygous state with another RYR1 loss of function variant in at least two individuals with RYR1-related myopathy (See patient 32 in Klein et al. 2011. PubMed ID: 21911697; See case ID 9166 in Supp. Table 2 Marinakis et al. 2021. PubMed ID: 34008892). This variant was also reported in an additional study as compound heterozygous in a patient with pediatric neuromuscular disease, but the second variant was not listed (See Supp. Table 2 in Herman et al. 2020. PubMed ID: 33146414). This variant was found in a patient in a cohort study of RYR1-related congenital myopathies, but no zygosity information was provided (Table 2 and Additional file 4, Fusto. 2022. PubMed ID: 35428369). This variant is reported in 0.027% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as likely pathogenic for autosomal recessive RYR1-related myopathy. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 417 of the RYR1 protein (p.Leu417Pro). This variant is present in population databases (rs764262446, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive congenital myopathy (PMID: 21911697, 22473935; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 544398). 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 RYR1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Congenital multicore myopathy with external ophthalmoplegia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

3billion

May 22, 2022

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000544398). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 22473935). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

See cases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Human Genetics Bochum, Ruhr University Bochum

Feb 13, 2023

ACMG criteria used to clasify this variant: PP3_STR, PS4_MOD, PM2_SUP -

Myopathy, RYR1-associated

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 08, 2024

Variant summary: RYR1 c.1250T>C (p.Leu417Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 207268 control chromosomes. c.1250T>C has been reported in the literature in individuals affected with congenital myopathies and central core disease in the compound heterozygous state (Klein_2011, Herman_2021, Rossi_2021, Marinakis_2021, Fusto_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21911697, 33146414, 33758288, 34008892, 35428369). ClinVar contains an entry for this variant (Variation ID: 544398). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Central core myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Oct 01, 2021

PM2, PM3, PP2, PP3 -

Malignant hyperthermia, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

This missense variant replaces leucine with proline at codon 417 of the RYR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.85, PMID: 27666373). This variant occurs in the N-terminal region (a.a. 1-552) of the RYR1 protein that is considered to be a hotspot for pathogenic variants that contribute to malignant hyperthermia susceptibility (PMID: 21118704). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 544398). This variant has been identified in 9/207268 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

.;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

T;T

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

M;M

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.6

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.88

MutPred

0.82

Gain of disorder (P = 0.0112);Gain of disorder (P = 0.0112);

MVP

0.99

MPC

1.2

ClinPred

0.83

GERP RS

4.3

Varity_R

0.92

gMVP

0.96

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over