Submissions for variant NM_020451.3(SELENON):c.1379C>T (p.Ser460Phe)

dbSNP: rs767530943

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000794147	SCV000933537	uncertain significance	Eichsfeld type congenital muscular dystrophy	2021-06-22	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with SELENON-related disease (PMID: 30642275, 29382405). ClinVar contains an entry for this variant (Variation ID: 641007). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is present in population databases (rs767530943, ExAC 0.002%). This sequence change replaces serine with phenylalanine at codon 460 of the SELENON protein (p.Ser460Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000794147	SCV003761211	likely pathogenic	Eichsfeld type congenital muscular dystrophy	2023-01-24	criteria provided, single submitter	curation	The p.Ser460Phe variant in SELENON has been reported in 4 individuals with SELENON-RM (PMID: 30642275, 29382405, Munell_2018) and has been identified in 0.002% (2/111376) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs767530943). 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#: 641007) and has been interpreted as a variant of uncertain significance by Invitae. Of the 3 affected individuals, 2 of those were homozygotes and 1 was a compound heterozygote that carried a reported pathogenic variant with unknown phase, which increases the likelihood that the p.Ser460Phe variant is pathogenic (VariationID: 4496; PMID: 30642275, 29382405, Munell_2018). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive SELENON-RM. ACMG/AMP Criteria applied: PM3_strong, PP3, PM2_supporting (Richards 2015).
Revvity Omics, Revvity	RCV000794147	SCV003819327	uncertain significance	Eichsfeld type congenital muscular dystrophy	2019-02-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526024	SCV005040074	uncertain significance	not specified	2024-03-07	criteria provided, single submitter	clinical testing	Variant summary: SELENON c.1379C>T (p.Ser460Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 245756 control chromosomes. c.1379C>T has been reported in the literature in individuals affected with Eichsfeld Type Congenital Muscular Dystrophy. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 641007). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.