NM_000540.3(RYR1):c.14524G>A (p.Val4842Met) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 21, 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:: RCV002247501.9

Allele description [Variation Report for NM_000540.3(RYR1):c.14524G>A (p.Val4842Met)]

NM_000540.3(RYR1):c.14524G>A (p.Val4842Met)

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.14524G>A (p.Val4842Met)

Other names:

NM_000540.2(RYR1):c.14524G>A

HGVS:

NC_000019.10:g.38580382G>A
NG_008866.1:g.151683G>A
NM_000540.3:c.14524G>AMANE SELECT
NM_001042723.2:c.14509G>A
NP_000531.2:p.Val4842Met
NP_000531.2:p.Val4842Met
NP_001036188.1:p.Val4837Met
LRG_766t1:c.14524G>A
LRG_766:g.151683G>A
LRG_766p1:p.Val4842Met
NC_000019.9:g.39071022G>A
NM_000540.2:c.14524G>A
P21817:p.Val4842Met
p.(Val4842Met)

Protein change:

V4837M; VAL4842MET

Links:

UniProtKB: P21817#VAR_045758; OMIM: 180901.0036; dbSNP: rs193922879

NCBI 1000 Genomes Browser:

rs193922879

Molecular consequence:

NM_000540.3:c.14524G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.14509G>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
SCV002519298	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Uncertain significance (May 4, 2022)	germline	clinical testing	Citation Link,
SCV005185142	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (May 21, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 20839240, 32403337, 21062345, 27854218, 28818389, 18253926, 21455645, 23553787 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002519298

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2019)

Uncertain significance
(May 4, 2022)

germline

clinical testing

Citation Link,

SCV005185142

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(May 21, 2024)

germline

clinical testing

PubMed (8)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

RYR1 mutations are a common cause of congenital myopathies with central nuclei.

Wilmshurst JM, Lillis S, Zhou H, Pillay K, Henderson H, Kress W, Müller CR, Ndondo A, Cloke V, Cullup T, Bertini E, Boennemann C, Straub V, Quinlivan R, Dowling JJ, Al-Sarraj S, Treves S, Abbs S, Manzur AY, Sewry CA, Muntoni F, Jungbluth H.

Ann Neurol. 2010 Nov;68(5):717-26. doi: 10.1002/ana.22119.

PubMed [citation]

PMID:: 20839240

Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain.

Gonzalez-Quereda L, Rodriguez MJ, Diaz-Manera J, Alonso-Perez J, Gallardo E, Nascimento A, Ortez C, Natera-de Benito D, Olive M, Gonzalez-Mera L, Munain AL, Zulaica M, Poza JJ, Jerico I, Torne L, Riera P, Milisenda J, Sanchez A, Garrabou G, Llano I, Madruga-Garrido M, Gallano P.

Genes (Basel). 2020 May 11;11(5). doi:pii: E539. 10.3390/genes11050539.

PubMed [citation]

PMID:: 32403337
PMCID:: PMC7288461

See all PubMed Citations (8)

Details of each submission

From Mendelics, SCV002519298.1

#	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	unknown	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, SCV005185142.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Variant summary: RYR1 c.14524G>A (p.Val4842Met) results in a conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251266 control chromosomes (gnomAD). c.14524G>A has been reported in the literature in individuals affected with Myopathy, RYR1-Associated (e.g. Monnier_2008, Wilmshurst_2010, Bevilacqua_2011, Zhou_2013, Punetha_2016, Abath Neto_2017, Gonzalez-Quereda_2020), and in many cases it was found in cis with the pathogenic variant c.10348-6C>G. It was also found in an individual with malignant hypothermia susceptibility who had another variant of uncertain significance (Kraeva_2011). These reports do not provide unequivocal conclusions about association of the variant with Myopathy, RYR1-Associated. 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: 18253926, 21062345, 23553787, 27854218, 21455645, 32403337, 20839240). ClinVar contains an entry for this variant (Variation ID: 133075). 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: Oct 13, 2024

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