NM_000540.3(RYR1):c.8327C>T (p.Ser2776Phe) AND RYR1-related disorder

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Jan 29, 2025
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:: RCV001088536.12

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]

Condition(s)

Name:: RYR1-related disorder
Synonyms:: RYR1-Related Disorders; RYR1-related condition
Identifiers:: MedGen: CN239331

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000660061	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 29, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000852832	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000660061

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Jan 29, 2025)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000852832

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 13, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000660061.9

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

#	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		not provided	not provided	not provided	not provided

From PreventionGenetics, part of Exact Sciences, SCV000852832.2

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

Description

The RYR1 c.8327C>T variant is predicted to result in the amino acid substitution p.Ser2776Phe. This variant was reported in two Malignant Hyperthermia (MH) patients and one patient with King Denborough syndrome (Broman et al. 2011. PubMedID: 21965348; Dowling et al. 2011. PubMedID: 21514828; Gonsalves et al. 2013. PubMedID: 24195946; Fiszer et al. 2015. PubMedID: 25658027). However, the pathogenicity was not clearly established in any of these cases and the asymptomatic mother of the King Denborough patient was heterozygous for the c.8327C>T variant. This suggests the c.8327C>T is less likely to be pathogenic for autosomal dominant RYR1-related disorders, but could be causative for a recessive RYR1-related myopathy. The c.8327C>T variant has been reported in control individuals of European ancestry with an allele frequency of about 0.1% (http://gnomad-old.broadinstitute.org/variant/19-38995965-C-T/). In summary, the clinical significance of the c.8327C>T variant is currently uncertain due to the absence of conclusive evidence.

#	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		not provided	not provided	not provided	not provided

Last Updated: Jun 22, 2025

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