Submissions for variant NM_000540.3(RYR1):c.957+5_957+29del

dbSNP: rs794726982

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000721748	SCV000224851	uncertain significance	not provided	2014-12-08	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000173706	SCV000540242	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Intronic deletion, possible weak splice impact; ExAC: 0.1% (12/11570) Latino chromosomes (does not pass quality filter)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000655587	SCV000777518	uncertain significance	RYR1-related disorder	2022-10-19	criteria provided, single submitter	clinical testing	This sequence change falls in intron 10 of the RYR1 gene. It does not directly change the encoded amino acid sequence of the RYR1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs752290298, gnomAD 0.06%). This variant has been observed in individual(s) with clinical features of RYR1-related conditions (PMID: 23628358; Invitae). ClinVar contains an entry for this variant (Variation ID: 193600). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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, part of Exact Sciences	RCV000721748	SCV000852879	uncertain significance	not provided	2016-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000721748	SCV001764682	uncertain significance	not provided	2020-09-15	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect
Johns Hopkins Genomics, Johns Hopkins University	RCV002281998	SCV002570274	uncertain significance	Neuromuscular disease	2022-03-27	criteria provided, single submitter	clinical testing	This RYR1 variant (rs794726982) is rare (<0.1%) in a large population dataset (gnomAD: 102/282552 total alleles; 0.036%; no homozygotes) and has been reported in ClinVar. This variant has been reported in two family members with exertional myalgia and rhabdomyolysis. This 25 bp deletion* is located in the splice donor region of intron 10. Bioinformatic analysis predicts that this variant would affect RNA splicing, although this has not been confirmed experimentally to our knowledge. Due to insufficient evidence, we consider the clinical significance of c.957+5_957+29del to be uncertain at this time.
Revvity Omics, Revvity	RCV000721748	SCV003812495	uncertain significance	not provided	2023-05-24	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003993854	SCV004812329	uncertain significance	Malignant hyperthermia, susceptibility to, 1	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change in RYR1 is an intronic variant located in intron 10. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.06% (74/128,986 alleles) in the European (non-Finnish) population. This variant has been reported in at least two families with recurrent rhabdomyolysis, and segregates with rhabdomyolysis in one of these families (PMID: 23628358, 25960145). The results from an in silico splicing predictor (SpliceAI) indicate that this variant supports neither a deleterious nor benign impact on the donor splice site of intron 10 of RYR1. Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none.