rs121908185

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM5PP5_Very_Strong

The NM_020451.3(SELENON):c.1397G>A(p.Arg466Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,613,804 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R466W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

SELENON
NM_020451.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 7.77

Variant links:

Genes affected

SELENON (HGNC:15999): (selenoprotein N) This gene encodes a glycoprotein that is localized in the endoplasmic reticulum. It plays an important role in cell protection against oxidative stress, and in the regulation of redox-related calcium homeostasis. Mutations in this gene are associated with early onset muscle disorders, referred to as SEPN1-related myopathy. SEPN1-related myopathy consists of 4 autosomal recessive disorders, originally thought to be separate entities: rigid spine muscular dystrophy (RSMD1), the classical form of multiminicore disease, desmin related myopathy with Mallory-body like inclusions, and congenital fiber-type disproportion (CFTD). This protein is a selenoprotein, containing the rare amino acid selenocysteine (Sec). Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon, rather than as a stop signal. A second stop-codon redefinition element (SRE) adjacent to the UGA codon has been identified in this gene (PMID:15791204). SRE is a phylogenetically conserved stem-loop structure that stimulates readthrough at the UGA codon, and augments the Sec insertion efficiency by SECIS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Dec 2016]

SELENON links:

ENSG00000255054 (HGNC:):

ENSG00000255054 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_020451.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-25813889-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1415561.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 1-25813890-G-A is Pathogenic according to our data. Variant chr1-25813890-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-25813890-G-A is described in Lovd as [Pathogenic]. Variant chr1-25813890-G-A is described in Lovd as [Pathogenic]. Variant chr1-25813890-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-25813890-G-A is described in Lovd as [Benign]. Variant chr1-25813890-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3 link	c.1397G>A	p.Arg466Gln	missense_variant	Exon 11 of 13	ENST00000361547.7	NP_065184.2	Q9NZV5-1
SELENON	NM_206926.2 link	c.1295G>A	p.Arg432Gln	missense_variant	Exon 10 of 12		NP_996809.1	Q9NZV5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7 link	c.1397G>A	p.Arg466Gln	missense_variant	Exon 11 of 13	1	NM_020451.3	ENSP00000355141.2		Q9NZV5-1
ENSG00000255054	ENST00000527604.1 link	n.-83G>A		upstream_gene_variant		5		ENSP00000457066.1		H3BT81

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000481

AC:

AN:

249298

Hom.:

AF XY:

0.0000665

AC XY:

AN XY:

135274

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000120

AC:

175

AN:

1461634

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000148

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000241

AC:

ExAC

AF:

0.0000579

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy

Pathogenic:7

Jan 24, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg466Gln variant in SELENON was identified by our study in the compound heterozygous state, along with a pathogenic variant, in 2 individuals with SELENON-RM. The variant has been reported in at least 10 individuals with SELENON-RM (PMID: 11528383, 12192640, 17951086, 18713863, 21670436, 23394784, 24988964, 30921636, 33652732, 33726816, 32661288), segregated with disease in 1 affected relative from 1 family (PMID: 11528383), and has been identified in 0.0086% (11/128492) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121908185). 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#: 4492) and has been interpreted as pathogenic by multiple submitters. Of the affected individuals, 2 of those were homozygotes, 3 were compound heterozygotes that carried reported likely pathogenic/pathogenic variants with unknown phase, and 2 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg466Gln variant is pathogenic (VariationID: 4494, 280493; PMID: 12192640, 33652732, 17951086, 21670436, 24988964). In vitro functional studies provide some evidence that the p.Arg466Gln variant may impact protein function (PMID: 19067361, 18713863). However, these types of assays may not accurately represent biological function. 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, this variant meets criteria to be classified as pathogenic for autosomal recessive SELENON-RM. ACMG/AMP Criteria applied: PP3, PM3_very-strong, PS3_moderate, PM2_supporting, (Richards 2015). -

Aug 26, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 24, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 30, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SELENON c.1397G>A (p.Arg466Gln) results in a 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 4.8e-05 in 249298 control chromosomes in gnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in SELENON causing SEPN1-related myopathies (4.8e-05 vs 0.0011). c.1397G>A has been reported in the literature in multiple individuals affected with features of SEPN1-related myopathies (congenital muscular dystrophies (MDC) or congenital myopathies) either at a compound heterozygous state with a second pathogenic variant, or at a homozygous state (example: Moghadaszadeh_2001, Schara_2008, Scoto_2011, Potulska-Chromik_2021, Maiti_2009). At least two publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in absence of SELENON protein and functionally diminished capacity of ryanodine binding, which can be rescued by Zebrafish SELENON (Jurynec_2008). Maiti_2009 also suggest this variant weakens the secondary structure of the Selenocysteine Redefinition Element, reduces selenocysteine insertion efficiency and SELENON RNA levels. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11528383, 33652732, 17951086, 21670436, 18713863, 17951086). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (pathogenic: n=8; likely pathogenic: n=1) Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 466 of the SELENON protein (p.Arg466Gln). This variant is present in population databases (rs121908185, gnomAD 0.009%). This missense change has been observed in individual(s) with congenital myopathy, multiminicore disease, and/or rigid spine syndrome (PMID: 11528383, 19067361, 23394784, 24988964; internal data). 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: 4492). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SELENON protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SELENON function (PMID: 18713863, 19067361). For these reasons, this variant has been classified as Pathogenic. -

Sep 25, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:4

Oct 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 11, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Western blot analysis showed that patients with the R466Q variant and another SELENON variant had significantly decreased levels of selenoprotein N as compared to wild type controls (Maiti et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35379322, 18713863, 12192640, 11528383, 17951086, 33726816, 30921636, 18313359, 24988964, 17365175, 12207930, 23394784, 33652732, 19067361, 35368679, 21670436) -

Apr 28, 2017

Athena Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 20, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Muscular dystrophy

Pathogenic:1

Mar 27, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg466Gln variant in SELENON has been reported in at least 11 unrelated individuals with muscular dystrophy with minicores or rigid spine myopathy, all of whom were homozygous or compound heterozygous with an additional SELENON variant (Moghadaszadeh 2001, Ferreiro 2002, Jurynec 2008, Schara 2008, Maiti 2009, Maggi 2013, Rudenskaia 2014, Broad Institute Rare Genomes Project). It has also been identified in 0.009% (11/128492) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), a frequency low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 4492). Computational prediction tools and conservation analyses support that this variant may impact the protein. Additionally, this variant occurs in the selenocysteine redefinition element (SRE) region, a region where multiple variants have been reported in association with disease and in vitro functional studies support an impact of this variant on protein function (Jurynec 2008, Maiti 2009). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive muscular dystrophy. ACMG/AMP Criteria applied: PM3_VeryStrong, PM1, PM2_Supporting, PS3_Moderate, PP3. -

SEPN1-related disorder

Pathogenic:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SEPN1 c.1397G>A (p.Arg466Gln) variant has been reported in six studies and is found in a total of eight patients with SEPN1-related disorders, including in one in a homozygous state and in seven in a compound heterozygous state (Moghadaszadeh et al. 2001; Ferreiro et al. 2002; Jurynec et al. 2008; Schara et al. 2008; Treves et al. 2008; Rudenskaia et al. 2014). The p.Arg466Gln variant was absent from 200 control chromosomes and is reported at a frequency of 0.00011 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional testing in muscle cell homogenates from an individual who was homozygous for the p.Arg466Gln variant, showed absence of expression of SEPN1 protein, and significantly reduced ryanodine binding capacity (Jurynec et al. 2008). In addition, Maiti et al. (2009) demonstrated a three-fold reduction in translation of a luciferase reporter construct in 293FT cells carrying the p.Arg466Gln variant compared to wild type. Based on the collective evidence, the p.Arg466Gln variant is classified as pathogenic for SEPN1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

.;T;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

1.6

.;L;.

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.9

N;N;N

REVEL

Pathogenic

0.73

Sift

Benign

0.069

T;T;T

Sift4G

Benign

0.23

T;T;T

Polyphen

0.95, 0.97

.;P;D

Vest4

0.97

MVP

0.94

MPC

0.93

ClinPred

0.31

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over