NM_000540.3(RYR1):c.5000G>A (p.Arg1667His) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 19, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000414466.3

Allele description [Variation Report for NM_000540.3(RYR1):c.5000G>A (p.Arg1667His)]

NM_000540.3(RYR1):c.5000G>A (p.Arg1667His)

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.5000G>A (p.Arg1667His)

HGVS:

NC_000019.10:g.38485655G>A
NG_008866.1:g.56956G>A
NM_000540.3:c.5000G>AMANE SELECT
NM_001042723.2:c.5000G>A
NP_000531.2:p.Arg1667His
NP_000531.2:p.Arg1667His
NP_001036188.1:p.Arg1667His
LRG_766t1:c.5000G>A
LRG_766:g.56956G>A
LRG_766p1:p.Arg1667His
NC_000019.9:g.38976295G>A
NM_000540.2:c.5000G>A

Protein change:

R1667H

Links:

dbSNP: rs138978909

NCBI 1000 Genomes Browser:

rs138978909

Molecular consequence:

NM_000540.3:c.5000G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.5000G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000492295	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Uncertain significance (Dec 13, 2016)	germline	clinical testing	Citation Link,
SCV004803870	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jan 19, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34008892, 28259615 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000492295

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Uncertain significance
(Dec 13, 2016)

germline

clinical testing

Citation Link,

SCV004803870

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jan 19, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders.

Marinakis NM, Svingou M, Veltra D, Kekou K, Sofocleous C, Tilemis FN, Kosma K, Tsoutsou E, Fryssira H, Traeger-Synodinos J.

Am J Med Genet A. 2021 Aug;185(8):2561-2571. doi: 10.1002/ajmg.a.62338. Epub 2021 May 19.

PubMed [citation]

PMID:: 34008892

Resequencing array for gene variant detection in malignant hyperthermia and butyrylcholinestherase deficiency.

Levano S, Gonzalez A, Singer M, Demougin P, Rüffert H, Urwyler A, Girard T.

Neuromuscul Disord. 2017 May;27(5):492-499. doi: 10.1016/j.nmd.2017.02.008. Epub 2017 Feb 21.

PubMed [citation]

PMID:: 28259615

Details of each submission

From GeneDx, SCV000492295.1

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

Description

The R1667H variant in the RYR1 gene has not been reported previously as a germline pathogenic variant, nor as a benign variant, to our knowledge. The R1667H variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1667H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R1667H as a variant of uncertain significance.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004803870.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: RYR1 c.5000G>A (p.Arg1667His) results in a non-conservative amino acid change located in the Ryanodine receptor, junctional solenoid domain (IPR048581) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 246574 control chromosomes, predominantly at a frequency of 0.00024 within the Non-Finnish European subpopulation in the gnomAD database. c.5000G>A has been reported in cis with a VUS variant p.Gly422Arg and in trans with an apparently pathogenic p.Leu417Pro in a female patient with Neuromuscular abnormalities through WES (example, Marinakis_2021). It has also been reported in a patient with unknown genetic condition (Levano_2017). These data do not allow any conclusion about variant significance. 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: 28259615, 34008892). ClinVar contains an entry for this variant (Variation ID: 373680, All VUS). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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: Nov 3, 2024

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