Submissions for variant NM_020451.3(SELENON):c.1427C>T (p.Ser476Leu)

gnomAD frequency: 0.00002  dbSNP: rs368377980

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497945	SCV000589850	likely pathogenic	not provided	2016-05-27	criteria provided, single submitter	clinical testing	The S476L variant has not been reported in an individual with a SEPN1-related myopathy, but functional studies demonstrated that S476L restored base pairing in the highly conserved stem loop structure of the Selenocysteine Redefinition Element when paired with another SEPN1 variant (c.1397 G>A) which was previously shown to affect this region and reduce read-through efficiency (Maiti et al., 2009). These studies suggest that S476L alone may destabilize the SRE similar to that of R466Q. The S476L variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000811605	SCV000951879	uncertain significance	Eichsfeld type congenital muscular dystrophy	2021-08-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265784	SCV002547532	uncertain significance	not specified	2022-05-18	criteria provided, single submitter	clinical testing	Variant summary: SELENON c.1427C>T (p.Ser476Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249402 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1427C>T in individuals affected with Eichsfeld Type Congenital Muscular Dystrophy has been reported. One publication reports experimental evidence evaluating an impact on protein function, however, the variant was not tested in isolation and thus this report does not allow convincing conclusions about the variant effect (Maiti_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000811605	SCV003761273	uncertain significance	Eichsfeld type congenital muscular dystrophy	2023-01-24	criteria provided, single submitter	curation	The p.Ser476Leu variant in SELENON has not been previously reported in the literature in individuals with SELENON-RM, but has been identified in 0.004% (5/113154) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs368377980). 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#: 432162) and has been interpreted as likely pathogenic by GeneDx and as a variant of uncertain significance by Invite, Genome Diagnostics Laboratory (Amsterdam University Medical Center), Diagnostic Laboratory (Department of Genetics, University Medical Center Groningen), Human Genetics - Radboudumc (Radboudumc). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ser476Leu variant is uncertain. ACMG/AMP Criteria applied: BP4, PM2_supporting, (Richards 2015).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000497945	SCV001744110	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000497945	SCV001807607	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000497945	SCV001959770	uncertain significance	not provided		no assertion criteria provided	clinical testing