Submissions for variant NM_020451.3(SELENON):c.249_250dup (p.Asp84fs)

dbSNP: rs1553198611

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000627410	SCV000748405	pathogenic	not provided	2022-09-14	criteria provided, single submitter	clinical testing	Observed in association with SEPN1-related myopathy in published literature (Villar-Quiles 2020; Ganapathy et al., 2019); Not observed at a significant frequency in large population cohorts (gnomAD); Frameshift 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; This variant is associated with the following publications: (PMID: 31069529, 21670436, 34838582, 32796131, 21131290)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799500	SCV000939165	pathogenic	Eichsfeld type congenital muscular dystrophy	2024-10-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp84Glyfs*17) 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). This variant is present in population databases (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of SELENON-related conditions (PMID: 32796131). ClinVar contains an entry for this variant (Variation ID: 523931). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000799500	SCV003761188	pathogenic	Eichsfeld type congenital muscular dystrophy	2023-01-24	criteria provided, single submitter	curation	The p.Asp84fs variant in SELENON has been reported in at least 1 individual, in a homozygous state, with SELENON-RM (PMID: 32796131, 34838582) and has been identified in 0.003% (1/30602) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs765917781). 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 GeneDx. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 84 and leads to a premature termination codon 17 amino acids downstream. This alteration is then 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, this variant meets criteria to be classified as pathogenic for autosomal recessive SELENON-RM. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3_supporting (Richards 2015).
Neuberg Centre For Genomic Medicine, NCGM	RCV000799500	SCV004101523	pathogenic	Eichsfeld type congenital muscular dystrophy		criteria provided, single submitter	clinical testing	The frameshift variant c.249_250dup (p.Asp84GlyfsTer17) in SELENON gene has been reported previously in homozygous state in a patient affected with congenital myopathy . The p.Asp84GlyfsTer17 variant has allele frequency 0.0004% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Castets P et al.). For these reasons, this variant has been classified as Pathogenic. The observed variant is also detected in the spouse.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000799500	SCV004807639	pathogenic	Eichsfeld type congenital muscular dystrophy	2024-03-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000799500	SCV005655138	pathogenic	Eichsfeld type congenital muscular dystrophy	2024-04-19	criteria provided, single submitter	clinical testing