Submissions for variant NM_020451.3(SELENON):c.565C>T (p.Arg189Ter)

gnomAD frequency: 0.00001  dbSNP: rs775713184

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001224095	SCV001396273	pathogenic	Eichsfeld type congenital muscular dystrophy	2023-06-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 952054). This premature translational stop signal has been observed in individual(s) with clinical features of SELENON-related conditions (PMID: 32528171). This variant is present in population databases (rs775713184, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg189*) in the SELENON gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SELENON are known to be pathogenic (PMID: 21131290, 21670436).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001224095	SCV002600329	likely pathogenic	Eichsfeld type congenital muscular dystrophy	2022-10-06	criteria provided, single submitter	clinical testing	Variant summary: SELENON c.565C>T (p.Arg189X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.1e-06 in 248170 control chromosomes (gnomAD). c.565C>T has been reported in the literature in individuals affected with Muscular Dystrophy (e.g. Topf_2020, Ogasawara_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters have assessed the variant since 2014: both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001224095	SCV003761442	likely pathogenic	Eichsfeld type congenital muscular dystrophy	2023-01-24	criteria provided, single submitter	curation	The p.Arg189Ter variant in SELENON has been reported in at least 1 individual with SELENON-RM (PMID: 32528171, 33184643) and has been identified in 0.006% (1/15464) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs775713184). 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#: 523931) and has been interpreted as pathogenic by Invitae and PerkinElmer Genomics. This nonsense variant leads to a premature termination codon at position 189 which is predicted to lead to a truncated or absent protein. Loss of function of the SELENON gene is an established disease mechanism in autosomal recessive SELENON-RM. 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: PVS1, PM2 (Richards 2015).
GeneDx	RCV003156323	SCV003845806	likely pathogenic	not provided	2022-09-21	criteria provided, single submitter	clinical testing	Reported in the published literature in association with muscle weakness (Topf et al., 2020; Lee et al., 2022); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21131290, 21670436, 32528171, 32796131, 30921636)