NM_000540.3(RYR1):c.12629A>G (p.Lys4210Arg) AND RYR1-related disorder

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 17, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000534293.17

Allele description [Variation Report for NM_000540.3(RYR1):c.12629A>G (p.Lys4210Arg)]

NM_000540.3(RYR1):c.12629A>G (p.Lys4210Arg)

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.12629A>G (p.Lys4210Arg)

HGVS:

NC_000019.10:g.38564963A>G
NG_008866.1:g.136264A>G
NM_000540.3:c.12629A>GMANE SELECT
NM_001042723.2:c.12614A>G
NP_000531.2:p.Lys4210Arg
NP_000531.2:p.Lys4210Arg
NP_000531.2:p.Lys4210Arg
NP_001036188.1:p.Lys4205Arg
LRG_766t1:c.12629A>G
LRG_766:g.136264A>G
LRG_766p1:p.Lys4210Arg
NC_000019.9:g.39055603A>G
NM_000540.2:c.12629A>G

Protein change:

K4205R

Links:

dbSNP: rs138932463

NCBI 1000 Genomes Browser:

rs138932463

Molecular consequence:

NM_000540.3:c.12629A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001042723.2:c.12614A>G - 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
SCV000659794	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 17, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25960145, 28492532
SCV005361640	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Uncertain significance (Aug 23, 2024)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000659794

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 17, 2022)

germline

clinical testing

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

SCV005361640

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Uncertain significance
(Aug 23, 2024)

germline

clinical testing

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

Snoeck M, van Engelen BG, Küsters B, Lammens M, Meijer R, Molenaar JP, Raaphorst J, Verschuuren-Bemelmans CC, Straathof CS, Sie LT, de Coo IF, van der Pol WL, de Visser M, Scheffer H, Treves S, Jungbluth H, Voermans NC, Kamsteeg EJ.

Eur J Neurol. 2015 Jul;22(7):1094-112. doi: 10.1111/ene.12713. Epub 2015 May 11.

PubMed [citation]

PMID:: 25960145

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000659794.7

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

Description

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 4210 of the RYR1 protein (p.Lys4210Arg). This variant is present in population databases (rs138932463, gnomAD 0.02%). This missense change has been observed in individual(s) with multiminicore disease (PMID: 25960145). ClinVar contains an entry for this variant (Variation ID: 93246). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RYR1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of 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

From PreventionGenetics, part of Exact Sciences, SCV005361640.1

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

Description

The RYR1 c.12629A>G variant is predicted to result in the amino acid substitution p.Lys4210Arg. This variant was reported in one patient with multiminicore disease (Snoeck et al. 2015. PubMed ID: 25960145, see Patient #53 in Table 3), but this patient also had four other rare missense variants in RYR1, and so the effect of the c.12629A>G (p.Lys4210Arg) variant alone is difficult to discern. This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic 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: Nov 10, 2024

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