1-25813899-G-A
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_020451.3(SELENON):c.1406G>A(p.Arg469Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R469W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_020451.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SELENON | NM_020451.3 | c.1406G>A | p.Arg469Gln | missense_variant | 11/13 | ENST00000361547.7 | |
SELENON | NM_206926.2 | c.1304G>A | p.Arg435Gln | missense_variant | 10/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SELENON | ENST00000361547.7 | c.1406G>A | p.Arg469Gln | missense_variant | 11/13 | 1 | NM_020451.3 | ||
SELENON | ENST00000374315.1 | c.1304G>A | p.Arg435Gln | missense_variant | 10/12 | 5 | P1 | ||
SELENON | ENST00000354177.9 | c.1235G>A | p.Arg412Gln | missense_variant | 10/12 | 5 | |||
SELENON | ENST00000494537.2 | c.1393G>A | p.Gly465Arg | missense_variant, NMD_transcript_variant | 11/13 | 3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249326Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135292
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461716Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727154
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Eichsfeld type congenital muscular dystrophy Pathogenic:4
Pathogenic, criteria provided, single submitter | research | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 17, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Jan 24, 2023 | 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. - |
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 24, 2023 | 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at