Submissions for variant NM_020451.3(SELENON):c.713dup (p.Asn238fs)

dbSNP: rs368104077

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000277917	SCV000231161	pathogenic	not provided	2015-04-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000277917	SCV000329609	pathogenic	not provided	2022-04-19	criteria provided, single submitter	clinical testing	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: 12192640, 19067361, 15792869, 17951086, 16498447, 27447704, 30612914, 30932294, 31321302, 31127727, 33652732)
Athena Diagnostics	RCV000277917	SCV000615148	pathogenic	not provided	2017-04-26	criteria provided, single submitter	clinical testing
Invitae	RCV000004751	SCV000949151	pathogenic	Eichsfeld type congenital muscular dystrophy	2023-11-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asn238Lysfs*63) 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 (rs750857935, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with SELENON-related conditions (PMID: 12192640, 15792869, 17951086, 27447704). ClinVar contains an entry for this variant (Variation ID: 4494). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000277917	SCV001250375	pathogenic	not provided	2022-08-01	criteria provided, single submitter	clinical testing	SELENON: PM3:Strong, PVS1:Strong, PM2
Institute of Human Genetics, University of Leipzig Medical Center	RCV000004751	SCV001440647	pathogenic	Eichsfeld type congenital muscular dystrophy	2024-02-26	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM3_STR,PM2_SUP; Identified as compund heterozygous with NM_020451.2:c.1282-13G>A
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000277917	SCV001447245	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Breda Genetics srl	RCV001353048	SCV001547494	pathogenic	Eichsfeld type congenital muscular dystrophy; Congenital myopathy with fiber type disproportion	2021-01-22	criteria provided, single submitter	clinical testing	The variant c.713dup (p.Asn238fs*62) in the SELENON gene is reported as a pathogenic for SELENON-related disorders in ClinVar (Variation ID: 4494) and as affecting function in the Global Variome shared LOVD v.3.0 database. The variant creates a shift in the reading frame, which is predicted to result in a premature stop codon 62 amino acids downstream, which is likely to result in a truncated protein or protein loss due to nonsense-mediated messenger decay (NMD). The variant was reported as pathogenic by Ferreiro et al., 2002 (PMID: 12192640) in two patients with multiminicore disease. In one patient the variant was in a state of homozygosity, in the other in compound heterozygosity with a missense mutation. In other studies (Stehlíková et al., 2017, PMID: 27447704; Tajsharghi et al., 2005, PMID: 15792869) the variant was identified in a compound heterozygous state with another mutation in a court of patients with congenital myopathies. In Schara et al., 2008 (PMID: 17951086) the variant was identified in heterozygosity in two patients with myopathy with delayed motor acquisition, hypotonia and lack of head control. It should be noted that the authors could not identify a second mutation in the other allele in these patients, and argue that a large deletion of one or more exons in the gene could constitute the mutation not identified by the sequencing technique used. The variant is reported with an estimated allelic frequency of 0.0001565 in gnomAD exomes and 0.0001912 in gnomAD genomes, with no homozygous individuals reported.
DASA	RCV000004751	SCV002061231	pathogenic	Eichsfeld type congenital muscular dystrophy	2022-01-05	criteria provided, single submitter	clinical testing	The c.713dup;p.(Asn238Lysfs*63) 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: 4494; OMIM: 606210.0006; PMID: 12192640; 27447704; 15792869; 17951086) - PS4. The variant is present at low allele frequencies population databases (rs368104077– gnomAD 0.01182%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000277917	SCV002502783	pathogenic	not provided	2021-05-26	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000004751	SCV002581322	pathogenic	Eichsfeld type congenital muscular dystrophy	2022-02-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001353048	SCV002788623	pathogenic	Eichsfeld type congenital muscular dystrophy; Congenital myopathy with fiber type disproportion	2021-08-11	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000004751	SCV003761453	pathogenic	Eichsfeld type congenital muscular dystrophy	2023-01-24	criteria provided, single submitter	curation	The homozygous p.Asn238fs variant in SELENON was identified by our study in one individual with SELENON-RM. The variant has been reported in at least 10 individuals with SELENON-RM (PMID: 12192640, 15792869, 19557870, 27447704, 30612914, 3093229, 33652732, 32661288, 16498447, 17951086), segregated with disease in 1 affected relative from 1 family (PMID: 33652732), and has been identified in 0.1% (14/10348) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs750857935). 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#: 4494) and has been interpreted as pathogenic by multiple submitters. Of the more than 10 affected individuals, at least 4 of those were homozygotes and 1 was a compound heterozygote that carried a reported pathogenic variants in trans, which increases the likelihood that the p.Asn238fs variant is pathogenic (VariationID: 95958; PMID: 12192640, 16498447, 19557870, 32661288, 33652732, 15792869). In vitro functional studies provide some evidence that the p.Asn238fs variant may impact protein function (PMID: 19067361). However, these types of assays may not accurately represent biological function. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 238 and leads to a premature termination codon 63 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, PS3_moderate, PM3_strong (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004751	SCV003928501	pathogenic	Eichsfeld type congenital muscular dystrophy	2023-04-05	criteria provided, single submitter	clinical testing	Variant summary: SELENON c.713dupA (p.Asn238LysfsX63) 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. The variant allele was found at a frequency of 0.00016 in 249200 control chromosomes (gnomAD). This frequency is not higher than estimated maximum expected for a pathogenic variant in SELENON causing Congenital Muscular Dystrophy (0.0011). The variant, c.713dupA, has been reported in the literature in several individuals affected with Muscular Dystrophy (Ferreiro_2002, Herasse_2007, Schara_2008, Villar-Quiles_2020), in at least one homozygous case, the absence of the protein was noted to be verified by western blot on patient derived fibroblasts (Herasse_2007). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000004751	SCV004238347	pathogenic	Eichsfeld type congenital muscular dystrophy	2023-02-10	criteria provided, single submitter	clinical testing
OMIM	RCV000004751	SCV000024927	pathogenic	Eichsfeld type congenital muscular dystrophy	2002-10-01	no assertion criteria provided	literature only