ClinVar Miner

Submissions for variant NM_020451.3(SELENON):c.1A>G (p.Met1Val)

gnomAD frequency: 0.00005  dbSNP: rs121908184
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482307 SCV000567022 pathogenic not provided 2015-06-26 criteria provided, single submitter clinical testing The c.1 A>G variant in the SEPN1 gene has been identified previously, both in the compound heterozygousand homozygous state, in patients with SEPN1-related disorders. Patient's presented with multiple featuresincluding rigid spine, nasal speech and various histological findings including minicores (Ferreiro et al., 2002;Maggi et al., 2013). The variant alters the initiator Methionine codon, and the resultant protein would bedescribed as p.Met1?" to signify that it is not known if the loss of Met1 means that all protein translation iscompletely prevented or if an abnormal protein is produced using an alternate Methionine initiator codon.Therefore, c.1 A>G is considered a pathogenic variant."
Labcorp Genetics (formerly Invitae), Labcorp RCV000004748 SCV000758294 pathogenic Eichsfeld type congenital muscular dystrophy 2025-01-01 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the SELENON mRNA. The next in-frame methionine is located at codon 85. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of the initiator codon has been observed in individuals with SELENON-related conditions (PMID: 12192640, 23394784, 28558865). ClinVar contains an entry for this variant (Variation ID: 4491). For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center RCV002288464 SCV002581201 pathogenic Congenital myopathy with fiber type disproportion 2021-11-15 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002504747 SCV002816949 likely pathogenic Eichsfeld type congenital muscular dystrophy; Congenital myopathy with fiber type disproportion 2021-11-15 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000004748 SCV006079730 likely pathogenic Eichsfeld type congenital muscular dystrophy 2025-04-29 criteria provided, single submitter curation The heterozygous p.Met1Val variant in SELENON has been reported in at least 7 individuals with rigid spine muscular dystrophy 1 (PMID: 12192640, 16365872, 23394784, 28558865), and has been identified in 0.013% (17406) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908184). 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. This variant has been reported in ClinVar (VCV000004491.15) and has been interpreted as pathogenic/likely pathogenic by multiple submitters. Of the 7 affected individuals, 2 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Met1Val variant is pathogenic (VCV000373075.21; PMID: 16365872, 28558865). This variant is located in the first amino acid and abolishes the methionine initiation codon. The next in-frame methionine is at amino acid residue 85 and there are multiple reported pathogenic/likely pathogenic variants in ClinVar upstream of this downstream methionine. Loss of function of the SELENON gene is an established disease mechanism in autosomal recessive rigid spine muscular dystrophy 1. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive rigid spine muscular dystrophy 1. ACMG/AMP Criteria PM3_strong, PVS1_moderate, PM2_supporting (Richards 2015).
OMIM RCV000004748 SCV000024924 pathogenic Eichsfeld type congenital muscular dystrophy 2006-03-01 no assertion criteria provided literature only

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