rs764262446

Variant names:

• chr19-38452824-T-C
• rs764262446
• NM_000540.3:c.1250T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP2 PP3_Moderate PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:2
• Conservation: PhyloP100: 5.63

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 Uncertain_significance. Variant got 4 ACMG points.

• PP2: Missense variant in the RYR1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 94 curated benign missense variants. Gene score misZ: 1.918 (below the threshold of 3.09). Trascript score misZ: 3.9788 (above the threshold of 3.09). GenCC associations: The gene is linked to 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: {Likely_pathogenic=5, Uncertain_significance=2, 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 rank	MANE	Protein	UniProt
RYR1	NM_000540.3	c.1250T>C	p.Leu417Pro	missense_variant	Exon 13 of 106	ENST00000359596.8	NP_000531.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8	c.1250T>C	p.Leu417Pro	missense_variant	Exon 13 of 106	5	NM_000540.3	ENSP00000352608.2
RYR1	ENST00000355481.8	c.1250T>C	p.Leu417Pro	missense_variant	Exon 13 of 105	1		ENSP00000347667.3
RYR1	ENST00000599547.6	n.1250T>C		non_coding_transcript_exon_variant	Exon 13 of 80	2		ENSP00000471601.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000434 AC: 9 AN: 207268 Hom.: 0 AF XY: 0.0000355 AC XY: 4 AN XY: 112616

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: 19 AN: 1439116 Hom.: 0 Cov.: 33 AF XY: 0.00000980 AC XY: 7 AN XY: 714082

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.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Jun 22, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 05, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RYR1-related disorder Pathogenic:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Sep 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Congenital multicore myopathy with external ophthalmoplegia Pathogenic:1

May 22, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

King Denborough syndrome;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1;C5830701:Central core myopathy Pathogenic:1

May 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases Pathogenic:1

Feb 13, 2023

Human Genetics Bochum, Ruhr University Bochum

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Myopathy, RYR1-associated Pathogenic:1

Mar 08, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Oct 01, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM3, PP2, PP3 -

Malignant hyperthermia, susceptibility to, 1 Uncertain:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	.;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Uncertain	0.76	T
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	D
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

Other links and lift over

dbSNP: rs764262446; hg19: chr19-38943464;