ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.4038C>A (p.Asn1346Lys) (rs777049924)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000657029 SCV000344618 uncertain significance not provided 2016-08-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000313458 SCV000412092 uncertain significance Neuromuscular disease, congenital, with uniform type 1 fiber 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000370505 SCV000412093 uncertain significance Central core myopathy 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000273611 SCV000412094 uncertain significance Malignant hyperthermia, susceptibility to, 1 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000331017 SCV000412095 uncertain significance Minicore myopathy 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000657029 SCV000589419 uncertain significance not provided 2018-04-10 criteria provided, single submitter clinical testing The N1346K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N1346K variant is observed in 14/70242 (0.02%) alleles from individuals of European background (Lek et al., 2016). The N1346K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000655552 SCV000777483 uncertain significance RYR1-Related Disorders 2019-07-08 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 1346 of the RYR1 protein (p.Asn1346Lys). The asparagine residue is weakly conserved and there is a moderate physicochemical difference between asparagine and lysine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in an individual affected with congenital myopathy (PMID: 29382405). However, in that individual this variant was observed in cis with a pathogenic allele, which suggests that this c.4038C>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 290117). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
PreventionGenetics,PreventionGenetics RCV000657029 SCV000852596 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000657029 SCV001151835 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing

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