NM_000540.3(RYR1):c.8327C>T (p.Ser2776Phe) AND not provided

Germline classification:: Conflicting classifications of pathogenicity (7 submissions)
Last evaluated:: Oct 1, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000721704.46

Allele description [Variation Report for NM_000540.3(RYR1):c.8327C>T (p.Ser2776Phe)]

NM_000540.3(RYR1):c.8327C>T (p.Ser2776Phe)

Genes:

LOC126862902:BRD4-independent group 4 enhancer GRCh37_chr19:38995830-38997029 [Gene]
RYR1:ryanodine receptor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19q13.2

Genomic location:

Preferred name:

NM_000540.3(RYR1):c.8327C>T (p.Ser2776Phe)

HGVS:

NC_000019.10:g.38505325C>T
NG_008866.1:g.76626C>T
NM_000540.3:c.8327C>TMANE SELECT
NM_001042723.2:c.8327C>T
NP_000531.2:p.Ser2776Phe
NP_000531.2:p.Ser2776Phe
NP_001036188.1:p.Ser2776Phe
LRG_766t1:c.8327C>T
LRG_766:g.76626C>T
LRG_766p1:p.Ser2776Phe
NC_000019.9:g.38995965C>T
NM_000540.2:c.8327C>T
NM_000540.3(RYR1):c.8327C>TMANE SELECT

Protein change:

S2776F

Links:

dbSNP: rs147707463

NCBI 1000 Genomes Browser:

rs147707463

Molecular consequence:

NM_000540.3:c.8327C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.8327C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000231315	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Apr 7, 2015)	germline	clinical testing	Citation Link,
SCV000892252	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Oct 1, 2024)	germline	clinical testing	Citation Link,
SCV001875161	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Mar 18, 2022)	germline	clinical testing	Citation Link,
SCV001932824	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV001952899	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV001972798	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV004224631	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 3, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21514828, 30788618, 25741868 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	4	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

King-Denborough syndrome with and without mutations in the skeletal muscle ryanodine receptor (RYR1) gene.

Dowling JJ, Lillis S, Amburgey K, Zhou H, Al-Sarraj S, Buk SJ, Wraige E, Chow G, Abbs S, Leber S, Lachlan K, Baralle D, Taylor A, Sewry C, Muntoni F, Jungbluth H.

Neuromuscul Disord. 2011 Jun;21(6):420-7. doi: 10.1016/j.nmd.2011.03.006. Epub 2011 Apr 22.

PubMed [citation]

PMID:: 21514828

The histopathological spectrum of malignant hyperthermia and rhabdomyolysis due to RYR1 mutations.

Knuiman GJ, Küsters B, Eshuis L, Snoeck M, Lammens M, Heytens L, De Ridder W, Baets J, Scalco RS, Quinlivan R, Holton J, Bodi I, Wraige E, Radunovic A, von Landenberg C, Reimann J, Kamsteeg EJ, Sewry C, Jungbluth H, Voermans NC.

J Neurol. 2019 Apr;266(4):876-887. doi: 10.1007/s00415-019-09209-z. Epub 2019 Feb 20.

PubMed [citation]

PMID:: 30788618
PMCID:: PMC6420893

See all PubMed Citations (3)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000231315.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV000892252.34

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	not provided

Description

RYR1: PP3, BS2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		4	not provided	not provided	not provided

From GeneDx, SCV001875161.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Identified in individuals with RYR1-related neuromuscular disorders; however, in these cases S2776F has been found in conjunction with other potentially pathogenic variants (Fiszer et al., 2015; Snoeck et al., 2015), or as a single variant that was found to be inherited from an unaffected parent (Dowling et al., 2011; Snoeck et al., 2015).; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25658027, 21965348, 25960145, 22705209, 27535533, 30788618, 32054689, 24195946, 21514828)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001932824.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001952899.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001972798.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV004224631.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jul 13, 2025

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