Submissions for variant NM_020451.3(SELENON):c.997_1000del (p.Val333fs)

dbSNP: rs886041686

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000299743	SCV000330414	pathogenic	not provided	2016-04-11	criteria provided, single submitter	clinical testing	The c.997_1000delGTGC pathogenic variant in the SEPN1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.997_1000delGTGC variant causes a frameshift starting with codon Valine 333, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Val333ProfsX6. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.997_1000delGTGC variant was not observed at any significant frequency in approximately 6400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.997_1000delGTGC as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045576	SCV001209438	pathogenic	Eichsfeld type congenital muscular dystrophy	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val333Profs*6) 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 individuals with congenital myopathy (PMID: 27447704, 33652732). ClinVar contains an entry for this variant (Variation ID: 280493). For these reasons, this variant has been classified as Pathogenic.
DASA	RCV001813775	SCV002061245	pathogenic	Congenital myopathy with fiber type disproportion	2022-01-05	criteria provided, single submitter	clinical testing	The c.997_1000del;p.(Val333Profs*?) is a null frameshift variant (NMD) in the SELENON gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(Clinvar ID: 280493; PMID: 27447704; 30921636) - PS4. The variant is present at low allele frequencies population databases (rs886041686– gnomAD 0.001314%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Val333Profs*?) was detected in trans with a pathogenic variant (PMID: 27447704; 30921636) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.
MGZ Medical Genetics Center	RCV001045576	SCV002581323	pathogenic	Eichsfeld type congenital muscular dystrophy	2022-02-16	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001045576	SCV003761089	pathogenic	Eichsfeld type congenital muscular dystrophy	2023-01-24	criteria provided, single submitter	curation	The p.Val333fs variant in SELENON has been reported in 6 individuals with SELENON-RM (PMID: 33652732, 27447704, 30921636), segregated with disease in 1 affected relative from 1 family (PMID: 33652732), and has been identified in 0.003% (3/113256) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1160635936). 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#: 280493) and has been interpreted as pathogenic by GeneDx, Invitae, GeneOne (DASA), and PerkinElmer Genomics. Of the 6 affected individuals, 2 of those were homozygotes, 1 was a compound heterozygote that carried a reported pathogenic variants in trans, and 2 were compound heterozygotes that carried reported pathogenic variants with unknown phase, which increases the likelihood that the p.Val333fs variant is pathogenic (VariationID: 4494; PMID: 27447704, 30921636). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 333 and leads to a premature termination codon 6 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_strong (Richards 2015).