Submissions for variant NM_020451.3(SELENON):c.1315C>T (p.Arg439Ter)

gnomAD frequency: 0.00002  dbSNP: rs377215510

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082011	SCV000225054	pathogenic	not provided	2013-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000082011	SCV000617297	pathogenic	not provided	2023-05-03	criteria provided, single submitter	clinical testing	Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19557870, 15792869, 25525159, 17951086, 30932294, 35599849, 32796131, 32906206)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792332	SCV000931620	pathogenic	Eichsfeld type congenital muscular dystrophy	2024-12-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg439*) 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 (rs377215510, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with multiminicore disease and autosomal recessive congenital myopathy (PMID: 15792869, 19557870). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 95958). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197254	SCV001367891	pathogenic	See cases	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2.
Mayo Clinic Laboratories, Mayo Clinic	RCV000082011	SCV001713798	pathogenic	not provided	2019-07-22	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3
Revvity Omics, Revvity	RCV000792332	SCV002020061	pathogenic	Eichsfeld type congenital muscular dystrophy	2019-07-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000792332	SCV002511858	pathogenic	Eichsfeld type congenital muscular dystrophy	2022-04-07	criteria provided, single submitter	clinical testing	Variant summary: SELENON c.1315C>T (p.Arg439X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.8e-05 in 247460 control chromosomes. c.1315C>T has been reported in the literature in individuals affected with Eichsfeld Type Congenital Muscular Dystrophy or similar disease. These data indicate that the variant may be associated with disease. Five 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000792332	SCV003761177	pathogenic	Eichsfeld type congenital muscular dystrophy	2023-01-24	criteria provided, single submitter	curation	The p.Arg439Ter variant in SELENON has been reported in 3 individuals with SELENON-RM (PMID: 15792869, 19557870, 30932294), segregated with disease in 1 affected relative from 1 family (PMID: 17951086), and has been identified in 0.00988% (3/30354) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs377215510). 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#: 95958) and has been interpreted as pathogenic by multiple submitters. Of the 3 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.Arg439Ter variant is pathogenic (PMID: 30932294). This nonsense variant leads to a premature termination codon at position 439 which is 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).
Fulgent Genetics, Fulgent Genetics	RCV000792332	SCV005655212	pathogenic	Eichsfeld type congenital muscular dystrophy	2024-04-24	criteria provided, single submitter	clinical testing