ClinVar Miner

Submissions for variant NM_020451.3(SELENON):c.878A>G (p.His293Arg)

gnomAD frequency: 0.00001  dbSNP: rs776738184
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000349806 SCV000357101 likely pathogenic SEPN1-related disorder 2017-04-28 criteria provided, single submitter clinical testing The SEPN1 c.878A>G (p.His293Arg) missense variant has been reported in three studies in which it is found in five individuals, including one homozygote and two compound heterozygotes with rigid spine muscular dystrophy, and two compound heterozygotes with multiminicore disease (Moghadaszadeh et al. 2001; Ferreiro et al. 2002; Mercuri et al. 2002). The variant was also identified in a heterozygous state in two unaffected parents but was absent from 200 control chromosomes. The p.His293Arg variant is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium, though this is based on only two alleles in a region of good sequence coverage so the variant is presumed to be rare. Based on the evidence, the p.His293Arg variant is classified as likely pathogenic for SEPN1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV002520484 SCV003523265 uncertain significance Eichsfeld type congenital muscular dystrophy 2022-09-03 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 297025). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individuals with congenital myopathy (PMID: 11528383, 12192640, 12207930). This variant is present in population databases (rs776738184, gnomAD 0.002%). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 293 of the SELENON protein (p.His293Arg).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002520484 SCV003761056 likely pathogenic Eichsfeld type congenital muscular dystrophy 2023-01-24 criteria provided, single submitter curation The p.His293Arg variant in SELENON has been reported in 4 individuals with SELENON-RM (PMID: 11528383, 12192640, 12207930, 16365872), segregated with disease in 2 affected relatives from 2 families (PMID: 11528383, 12192640), and has been identified in 0.002% (2/113176) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs776738184). 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 also been reported in ClinVar (Variation ID#: 297025) and has been interpreted as likely pathogenic by Illumina Laboratory Services (Illumina). Of the 4 affected individuals, 1 was a homozygote and 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.His293Arg variant is pathogenic (PMID: 12207930, 11528383; Clinvar ID: 4492). 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, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive SELENON-RM. ACMG/AMP Criteria applied: PM2, PM3, PP1, PP3 (Richards 2015).
OMIM RCV002520484 SCV003918862 pathogenic Eichsfeld type congenital muscular dystrophy 2001-09-01 no assertion criteria provided literature only

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