Submissions for variant NM_000540.3(RYR1):c.14761TTC[3] (p.Phe4924del)

dbSNP: rs1064794572

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479874	SCV000569486	pathogenic	not provided	2023-09-27	criteria provided, single submitter	clinical testing	Identified in a 9 year old male patient with a congenital myopathy characterized by delayed motor development, facial weakness, muscle weakness, and hypermobility; however parental testing was not completed and further characterization of the variant was not performed (Snoeck et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25960145, 16084090, 35548885, 36516687, 20681998, 33767344)
Genetic Services Laboratory, University of Chicago	RCV000479874	SCV000596910	likely pathogenic	not provided	2016-03-04	criteria provided, single submitter	clinical testing
Invitae	RCV000548242	SCV000659858	pathogenic	RYR1-related disorder	2023-11-06	criteria provided, single submitter	clinical testing	This variant, c.14770_14772del, results in the deletion of 1 amino acid(s) of the RYR1 protein (p.Phe4924del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with congenital myopathy (PMID: 25960145; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 420588). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000479874	SCV000852455	likely pathogenic	not provided	2016-08-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000479874	SCV001501719	likely pathogenic	not provided	2023-01-01	criteria provided, single submitter	clinical testing	RYR1: PM1, PM2, PM6, PM4:Supporting, PS4:Supporting
MGZ Medical Genetics Center	RCV002289631	SCV002579380	likely pathogenic	Central core myopathy	2021-09-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002489160	SCV002779384	likely pathogenic	Central core myopathy; Malignant hyperthermia, susceptibility to, 1; Congenital multicore myopathy with external ophthalmoplegia; Congenital myopathy with fiber type disproportion; King Denborough syndrome	2022-04-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000479874	SCV003810538	uncertain significance	not provided	2021-05-25	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV002289631	SCV004048243	pathogenic	Central core myopathy		criteria provided, single submitter	clinical testing	The inframe deletion variant c.14770_14772del (p.Phe4924del) in RYR1 gene has been reported in an individual affected with congenital myopathy (Snoeck M et.al., 2015). Functional studies reveal a damaging effect (Xu Le et al,2020).This p.Phe4924del causes deletion of amino acid Phenylalanine at position 4924. This variant has been reported to the ClinVar database as Pathogenic. The p.Phe4924del variant is novel (not in any individuals) in gnomAD and 1000 Genomes. For these reasons, this variant has been classified as Pathogenic
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV002289631	SCV004101068	likely pathogenic	Central core myopathy	2023-11-02	no assertion criteria provided	clinical testing