Submissions for variant NM_020451.3(SELENON):c.402_403+2del

dbSNP: rs773670891

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000554237	SCV000634411	likely pathogenic	Eichsfeld type congenital muscular dystrophy	2023-11-27	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 3 (c.402_403+2del) of the SELENON gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SELENON are known to be pathogenic (PMID: 21131290, 21670436). This variant is present in population databases (rs773670891, gnomAD 0.1%). This variant has been observed in individual(s) with clinical features of SELENON-related conditions (PMID: 31847883). ClinVar contains an entry for this variant (Variation ID: 461633). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001562761	SCV001785577	likely pathogenic	not provided	2021-03-12	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Deletions involving coding exons of this gene are a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 21131290, 21670436)
Revvity Omics, Revvity	RCV000554237	SCV002019168	likely pathogenic	Eichsfeld type congenital muscular dystrophy	2022-01-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002506322	SCV002810502	pathogenic	Eichsfeld type congenital muscular dystrophy; Congenital myopathy with fiber type disproportion	2021-11-04	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000554237	SCV003761295	uncertain significance	Eichsfeld type congenital muscular dystrophy	2023-01-24	criteria provided, single submitter	curation	The c.402_403+2del variant in SELENON has not been previously reported in the literature in individuals with SELENON-RM but has been identified in 0.1% (13/9840) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs773670891). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 461633) and has been interpreted as likely pathogenic by Invitae, GeneDx, and PerkinElmer Genomics. Conservation and expression data indicate that this exon might not be biologically relevant for this disease, and therefore this variant is not expected to result in loss of function of SELENON. In summary, the clinical significance of the c.402_403+2del variant is uncertain. ACMG/AMP Criteria applied: none (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000554237	SCV003933982	likely pathogenic	Eichsfeld type congenital muscular dystrophy	2023-05-09	criteria provided, single submitter	clinical testing	Variant summary: SELENON c.402_403+2delGAGT is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00011 in 35924 control chromosomes (gnomAD). c.402_403+2delGAGT has been reported in the literature in a sudden death of a young individual (Salfati_2019). This report does not provide unequivocal conclusions about association of the variant with Eichsfeld Type Congenital Muscular Dystrophy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31847883). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic.