ClinVar Miner

Submissions for variant NM_000540.2(RYR1):c.14761_14763TTC[5] (p.Phe4924dup) (rs1064794572)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000721399 SCV000619989 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the RYR1 gene. The c.14770_14772dupTTC variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.14770_14772dupTTC variant is not observed at significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.14770_14772dupTTC variant results in an in-frame duplication of a single Phenylalanine residue, denoted p.Phe4924dup. This variant occurs at a position that is conserved. However, in-frame deletions and duplications have not been reported in the Human Gene Mutation Database in association with RYR1-related disorders (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
PreventionGenetics,PreventionGenetics RCV000721399 SCV000852456 uncertain significance not provided 2016-04-12 criteria provided, single submitter clinical testing
Invitae RCV000792265 SCV000931549 uncertain significance RYR1-Related Disorders 2018-08-22 criteria provided, single submitter clinical testing This variant, c.14770_14772dupTTC, results in the insertion of 1 amino acid(s) to the RYR1 protein (p.Phe4924dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RYR1-related disease. ClinVar contains an entry for this variant (Variation ID: 451311). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This missense change is located in a region of the RYR1 protein where a significant number of previously reported RYR1 missense mutations are found (PMID: 16084090). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. 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.

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