Submissions for variant NM_020451.3(SELENON):c.1406G>A (p.Arg469Gln)

dbSNP: rs779162837

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000551007	SCV000634399	pathogenic	Eichsfeld type congenital muscular dystrophy	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 469 of the SELENON protein (p.Arg469Gln). This variant is present in population databases (no rsID available, gnomAD 0.02%). This missense change has been observed in individual(s) with SELENON-related myopathy (PMID: 19067361, 30932294, 32154989; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg435Gln. ClinVar contains an entry for this variant (Variation ID: 461629). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SELENON protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000551007	SCV003761263	likely pathogenic	Eichsfeld type congenital muscular dystrophy	2023-01-24	criteria provided, single submitter	curation	The p.Arg469Gln variant in SELENON has been reported in 6 individuals with SELENON-RM (PMID: 32154989, 19067361, 34867752, 30932294, Concentino_2016) and has been identified in 0.02% (4/17976) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs779162837). 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#: 461629) and has been interpreted as pathogenic by Invitae. Of the 6 affected individuals, 2 of those were homozygotes, and 1 was a compound heterozygote that carried a reported likely pathogenic variant with unknown phase, which increases the likelihood that the p.Arg469Gln variant is pathogenic (PMID: 32154989, 19067361). 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, the clinical significance of the p.Arg469Gln variant is uncertain. ACMG/AMP Criteria applied: PP3, PM3 (Richards 2015).
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000551007	SCV004171973	likely pathogenic	Eichsfeld type congenital muscular dystrophy	2023-01-24	criteria provided, single submitter	clinical testing	The missense c.1406G>A (p.Arg469Gln) variant in SELENON gene has been reported previously with autosomal recessive inheritance in individuals affected with SELENON-related disorders (Maiti et al. 2009; Bachmann et al. 2019; Tsang et al. 2020). The p.Arg469Gln variant is reported with an allele frequency of 0.002% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. The amino acid change p.Arg469Gln in SELENON is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant has been reported to the ClinVar database as Pathogenic / Likely Pathogenic. The amino acid Arg at position 469 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. Missense change in this region is reported to affect the protein function (Maiti et al. 2009). Additional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000551007	SCV004804675	pathogenic	Eichsfeld type congenital muscular dystrophy	2024-03-17	criteria provided, single submitter	research