ClinVar Miner

Submissions for variant NM_020451.3(SELENON):c.1501-1G>A

gnomAD frequency: 0.00001  dbSNP: rs750138587
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000815877 SCV000956355 likely pathogenic Eichsfeld type congenital muscular dystrophy 2022-03-18 criteria provided, single submitter clinical testing In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 658952). This variant has not been reported in the literature in individuals affected with SELENON-related conditions. This variant is present in population databases (rs750138587, gnomAD 0.01%). This sequence change affects an acceptor splice site in intron 11 of the SELENON 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 SELENON are known to be pathogenic (PMID: 21131290, 21670436).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000815877 SCV003761296 uncertain significance Eichsfeld type congenital muscular dystrophy 2023-01-24 criteria provided, single submitter curation The c.1501-1G>A variant in SELENON has not been previously reported in the literature in individuals with SELENON-RM but has been identified in 0.01% (2/17978) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs750138587). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 658952) and has been interpreted as likely pathogenic by Invitae. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. This variant is adjacent to an in-frame exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the SELENON gene is an established disease mechanism in autosomal recessive SELENON-RM. In summary, the clinical significance of the c.1501-1G>A variant is uncertain. ACMG/AMP Criteria applied: PVS1_moderate (Richards 2015).

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