19-38473726-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000540.3(RYR1):c.4115C>T(p.Ala1372Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,543,788 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1372E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

RYR1
NM_000540.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:2

Conservation

PhyloP100: -0.0510

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

malignant hyperthermia, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, Ambry Genetics
congenital multicore myopathy with external ophthalmoplegia
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
RYR1-related myopathy
Inheritance: AR, AD Classification: DEFINITIVE Submitted by: ClinGen
central core myopathy
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
King-Denborough syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
malignant hyperthermia of anesthesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive centronuclear myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
benign Samaritan congenital myopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital myopathy with myasthenic-like onset
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
lethal multiple pterygium syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RYR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.076971054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RYR1	NM_000540.3 link	c.4115C>T	p.Ala1372Val	missense_variant	Exon 28 of 106	ENST00000359596.8	NP_000531.2	P21817-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RYR1	ENST00000359596.8 link	c.4115C>T	p.Ala1372Val	missense_variant	Exon 28 of 106	5	NM_000540.3	ENSP00000352608.2		P21817-1

Frequencies

GnomAD3 genomes

AF:

0.000244

AC:

AN:

151652

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000486

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000221

AC:

AN:

139990

AF XY:

0.000158

show subpopulations

Gnomad AFR exome

AF:

0.000155

Gnomad AMR exome

AF:

0.000299

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000419

Gnomad OTH exome

AF:

0.000246

GnomAD4 exome

AF:

0.000236

AC:

329

AN:

1392136

Hom.:

Cov.:

AF XY:

0.000233

AC XY:

160

AN XY:

686428

show subpopulations

African (AFR)

AF:

0.0000960

AC:

AN:

31238

American (AMR)

AF:

0.000289

AC:

AN:

34558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24950

East Asian (EAS)

AF:

0.00

AC:

AN:

35680

South Asian (SAS)

AF:

0.0000633

AC:

AN:

78978

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47696

Middle Eastern (MID)

AF:

0.000557

AC:

AN:

5388

European-Non Finnish (NFE)

AF:

0.000276

AC:

297

AN:

1076060

Other (OTH)

AF:

0.000191

AC:

AN:

57588

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000244

AC:

AN:

151652

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

AN XY:

74054

show subpopulations

African (AFR)

AF:

0.0000485

AC:

AN:

41264

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5112

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000486

AC:

AN:

67848

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000265

Hom.:

Bravo

AF:

0.000219

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000320

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000669

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Sep 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 13, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 11, 2016

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 06, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 22, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Malignant hyperthermia, susceptibility to, 1

Uncertain:3

May 22, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces alanine with valine at codon 1372 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RYR1-related disorders in the literature. This variant has been identified in 36/170906 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. -

Sep 17, 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 alanine with valine at codon 1372 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with malignant hyperthermia in the literature. This variant has been identified in 36/170906 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. -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Uncertain:1

Feb 16, 2024

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RYR1 c.4115C>T (p.Ala1372Val) results in a non-conservative amino acid change located in the B30.2/SPRY domain (IPR001870) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00024 in 1543788 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4115C>T in individuals affected with Myopathy, RYR1-Associated and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 374135). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Congenital multicore myopathy with external ophthalmoplegia

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Congenital myopathy with fiber type disproportion

Uncertain:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Uncertain significance. -

Congenital myasthenic syndrome

Uncertain:1

Jan 15, 2015

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Central core myopathy

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RYR1-related disorder

Benign:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.32

CADD

Benign

5.7

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.34

.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.65

T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.077

T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

-1.0

N;N

PhyloP100

-0.051

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.63

N;N

REVEL

Benign

0.19

Sift

Benign

0.29

T;T

Polyphen

0.13

B;B

Vest4

0.066

MVP

0.74

MPC

0.31

ClinPred

0.011

GERP RS

-0.95

Varity_R

0.029

gMVP

0.31

Mutation Taster

=77/23

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over