ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.10961T>C (p.Leu3654Pro)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002789974 SCV003761245 uncertain significance RYR1-related myopathy 2023-01-25 criteria provided, single submitter curation The heterozygous p.Leu3654Pro variant in RYR1 was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 285009), in one individual with congenital myopathy. Trio exome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 285009). The p.Leu3654Pro variant has not been previously reported in individuals with RYR1-related myopathy but has been identified in 0.0007% (2/264690) chromosomes in TopMed Bravo (https://bravo.sph.umich.edu). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. The affected individual identified by our study was a compound heterozygote that carried a likely pathogenic variant in trans (ClinVar Variation ID: 285009), which increases the likelihood that the p.Leu3654Pro variant is pathogenic. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Leu3654Pro variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PM3, PP3 (Richards 2015).
Ambry Genetics RCV004244484 SCV004945794 uncertain significance Inborn genetic diseases 2024-01-08 criteria provided, single submitter clinical testing The c.10961T>C (p.L3654P) alteration is located in exon 75 (coding exon 75) of the RYR1 gene. This alteration results from a T to C substitution at nucleotide position 10961, causing the leucine (L) at amino acid position 3654 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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