ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.14804-1G>T

dbSNP: rs193922894
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002514601 SCV003288003 likely pathogenic RYR1-related disorder 2022-08-31 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 102 of the RYR1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in RYR1 are known to be pathogenic (PMID: 20583297, 20839240, 23919265, 28818389). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with RYR1-related conditions (PMID: 18253926, 25960145, 29417091). ClinVar contains an entry for this variant (Variation ID: 133092). Studies have shown that disruption of this splice site alters RYR1 gene expression (PMID: 18253926). Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 18253926). For these reasons, this variant has been classified as Pathogenic.
All of Us Research Program, National Institutes of Health RCV003997315 SCV004830986 uncertain significance Malignant hyperthermia, susceptibility to, 1 2023-06-26 criteria provided, single submitter clinical testing This variant causes a G to T nucleotide substitution at the -1 position of intron 102 of the RYR1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has not been reported in individuals affected with autosomal dominant malignant hyperthermia in the literature, although it is associated with other phenotype(s) (ClinVar variation ID: 136839; and PMIDs: 18253926, 29417091, 33060286). Loss of RYR1 function due to haploinsufficiency is associated with congenital myopathy (https://clinicalgenome.org/), but it is not an established disease mechanism for autosomal dominant malignant hyperthermia susceptibility. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance for autosomal dominant malignant hyperthermia.
RYR1 database RCV000119563 SCV000154470 not provided not provided no assertion provided not provided

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