Submissions for variant NM_020451.3(SELENON):c.863_864del (p.Val288fs)

dbSNP: rs1184282261

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001214700	SCV001386397	pathogenic	Eichsfeld type congenital muscular dystrophy	2019-06-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val288Aspfs*12) in the SELENON gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed with a second variant in individuals with clinical features of SELENON-related disease (PMID: 16900928). Loss-of-function variants in SELENON are known to be pathogenic (PMID: 21131290, 21670436). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001214700	SCV002020057	pathogenic	Eichsfeld type congenital muscular dystrophy	2019-05-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001214700	SCV002766419	likely pathogenic	Eichsfeld type congenital muscular dystrophy	2022-11-09	criteria provided, single submitter	clinical testing	Variant summary: SELENON (SEPN1) c.863_864delTG (p.Val288AspfsX12) 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. At least one truncation downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 249206 control chromosomes (gnomAD). c.863_864delTG has been reported in the literature in the compound heterozygous state in at least two individuals affected with Eichsfeld Type Congenital Muscular Dystrophy (Rigid Spine Muscular Dystrophy) (e.g. Sponholz_2006, Villar-Quiles_2020). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories 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	RCV001214700	SCV003760990	likely pathogenic	Eichsfeld type congenital muscular dystrophy	2023-01-24	criteria provided, single submitter	curation	The p.Val288fs variant in SELENON has been reported in 1 individual in the compound heterozygous state with SELENON-RM (PMID: 16900928) and has been identified in 0.0009% (1/113024) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1445226778). 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#: 944327) and has been interpreted as pathogenic by Invitae and PerkinElmer Genomics. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 288 and leads to a premature termination codon 12 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, 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).