rs121908188

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_020451.3(SELENON):c.943G>A(p.Gly315Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,613,918 control chromosomes in the GnomAD database, including 1 homozygotes. 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. G315R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00053 ( 1 hom. )

Consequence

SELENON
NM_020451.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26O:1

Conservation

PhyloP100: 8.12

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-25809754-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

PP5

Variant 1-25809753-G-A is Pathogenic according to our data. Variant chr1-25809753-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-25809753-G-A is described in Lovd as [Pathogenic]. Variant chr1-25809753-G-A is described in Lovd as [Pathogenic]. Variant chr1-25809753-G-A is described in Lovd as [Benign]. Variant chr1-25809753-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-25809753-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.943G>A	p.Gly315Ser	missense_variant	Exon 7 of 13	ENST00000361547.7	NP_065184.2	Q9NZV5-1
SELENON	NM_206926.2 link	c.841G>A	p.Gly281Ser	missense_variant	Exon 6 of 12		NP_996809.1	Q9NZV5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SELENON	ENST00000361547.7 link	c.943G>A	p.Gly315Ser	missense_variant	Exon 7 of 13	1	NM_020451.3	ENSP00000355141.2	Q9NZV5-1
SELENON	ENST00000374315.1 link	c.841G>A	p.Gly281Ser	missense_variant	Exon 6 of 12	5		ENSP00000363434.1	Q9NZV5-2
SELENON	ENST00000354177.9 link	c.772G>A	p.Gly258Ser	missense_variant	Exon 6 of 12	5		ENSP00000346109.5	H9KV50
SELENON	ENST00000494537.2 link	n.841G>A		non_coding_transcript_exon_variant	Exon 6 of 13	3		ENSP00000508308.1	A0A804HLD6

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.000529

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000176

AC:

AN:

249510

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

135396

show subpopulations

Gnomad AFR exome

AF:

0.0000645

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000930

Gnomad NFE exome

AF:

0.000362

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000532

AC:

777

AN:

1461814

Hom.:

Cov.:

AF XY:

0.000490

AC XY:

356

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.000679

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000289

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.000169

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:

0.000529

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000419

Hom.:

Bravo

AF:

0.000287

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000233

AC:

ESP6500EA

AF:

0.000588

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy

Pathogenic:12

May 04, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous p.Gly315Ser variant in SELENON (also referred to as SEPN1) was identified by our study in the compound heterozygous state, along with an exonic deletion of uncertain significance, in one individual with SELENON-RM. This variant has been reported in at least 10 individuals with SELENON-RM (PMID: 16365872, 12192640, 17951086), segregated with disease in 5 affected relatives from 4 families (PMID: 12192640, 16365872), and has been identified in 0.037% (48/128676) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs121908188). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 4496) and has been interpreted as pathogenic/likely pathogenic by multiple labs. Of the many affected individuals, 2 of those were homozygotes and 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Gly315Ser variant is pathogenic (Variation ID: 4492,95958; PMID: 12192640, 17951086). In vitro functional studies provide some evidence that the variant may slightly impact protein function (PMID: 19067361). 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: PP1_strong, PM3_strong, PP3, PS3_supporting (Richards 2015). -

Mar 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 12, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_Supporting, PM2, PM3_Very Strong, PP3 -

Dec 12, 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.943G>A (p.Gly315Ser) 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 0.00018 in 249510 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SELENON causing Eichsfeld Type Congenital Muscular Dystrophy (0.00018 vs 0.0011), allowing no conclusion about variant significance. c.943G>A has been reported in the literature as biallelic homozygous or compound heterozygous genotypes in multiple individuals affected with features of Eichsfeld Type Congenital Muscular Dystrophy (example, Ferreiro_2004, Nicolau_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15122708, 17204937, 31321302). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Aug 12, 2024

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

comp. het. with chr1:25809095-25809095 (c. 817) G>A; two affected sisters, both with both variants -

Mar 04, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

The SEPN1 variant (c. 943G>A) was identified in several patients in the literature and a disease-specific database (Ferreiro et al. 2002, PMID: 12192640; Venance et al. 2005, PMID: 15668457; Clarke et al. 2006, PMID: 16365872; Schara et al. 2008, PMID: 17951086; Maggi et al. 2013, PMID: 23394784). Protein levels tested from fibroblast cells of an affected patient showed reduced activity of the protein (Maiti et al. 2009, PMID: 19067361). -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 315 of the SELENON protein (p.Gly315Ser). This variant is present in population databases (rs121908188, gnomAD 0.04%). This missense change has been observed in individual(s) with SELENON-related conditions (PMID: 12192640, 16365872, 17951086, 23394784; internal data). 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. ClinVar contains an entry for this variant (Variation ID: 4496). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Apr 20, 2023

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (G>A) at coding nucleotide 943 of the SELENON gene that results in a glycine to serine amino acid change at residue 315 of the SELENON protein. This is a previously reported variant (ClinVar) that has been observed in the literature in many individuals with SELENON-related disorders in both the homozygous and compound heterozygous state (PMID: 12192640, 16365872, 19067361, 23394784, 30932294, 32796131, 34867752). This variant is present in the gnomAD population database (51 of 280900 alleles or 0.018%). Bioinformatic tools predict that this variant would be damaging, and the Gly315 residue is highly conserved across the vertebrate species examined. Protein expression studies found that this variant along with a second missense variant led to an approximate 80% decrease in protein expression in patient fibroblasts (PMID: 19067361). Given the currently available evidence, we consider this variant to be pathogenic. ACMG Criteria: PP3, PP5, PS3, PS4 -

Jul 11, 2024

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 10, 2025

Neurogenomics Lab, Neuroscience Institute, University Of Cape Town

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM2_supporting: This variant is present in population databases. The highest MAF observed across all subpopulations of gnomAD, ExAC, 1000 Genomes and ESP is 0.00059 (5/8502 alleles, no homozygous observations). PP3_strong: REVEL score is 0.949. PS3_supporting: functional studies provide supportive evidence that the variant has a damaging effect on the gene or gene product (PMID 19067361). PP1_strong: ≥3 informative meioses across ≥1 family (PMID 12192640, 16365872). PM3_strong: Detected in trans with pathogenic variant- total 2.5 points (PMID 17951086, 12192640, 16365872. Sequencing funded by the International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD): https://www.ucl.ac.uk/genomic-medicine-neuromuscular-diseases/. -

Jun 13, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly315Ser variant in SEPN1 has been reported in 8 individuals with a conge nital myopathy, including 6 who were homozygous and 2 compound heterozygous with another pathogenic allele (Ferreiro 2002, Clarke 2006, Maiti 2009, Maggi 2013), and segregated in 5 affected relatives (Ferreiro 2002, Clarke 2006). This varia nt has been identified in 0.04% (50/126676) of European chromosomes by the Genom e Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908 188) and in ClinVar (Variation ID: 4496). Although this variant has been seen i n the general population, its frequency is low enough to be consistent with a re cessive carrier frequency. Computational prediction tools and conservation analy sis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Additionally, analysis using fibroblast cells of an affected patient showed an impact on protein activity (Ma iti 2009). In summary, this variant is pathogenic for congenital muscular dystro phy with spinal rigidity in an autosomal recessive manner. ACMG/AMP Criteria app lied: PM3_Strong; PP1_Strong; PP3. -

Jun 01, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:6

Apr 01, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15668457, 20301436, 23394784, 12192640, 16365872, 15122708, 28688748, 31127727, 31321302, 30932294, 31561939, 33726816, 37864479, 17951086, 37807786) -

Jan 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 24, 2014

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2_moderate, PM3_strong, PS3_supporting, PS4 -

Dec 03, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2015

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myopathy with fiber type disproportion

Pathogenic:3Other:1

Dec 03, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Mar 04, 2015

Division of Human Genetics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

May 24, 2019

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion

Pathogenic:2

May 06, 2019

Undiagnosed Diseases Network, NIH

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SEPN1-related disorder

Pathogenic:1

Oct 16, 2018

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of available literature, the SEPN1 c.943G>A (p.Gly315Ser) missense variant has been identified in a homozygous state in 12 individuals and in a compound heterozygous state in four individuals from a total of ten unrelated families, with phenotypes including multiminicore disease, rigid spine muscular dystrophy, congenital fiber-type disproportion, and nemaline myopathy (Ferreiro et al. 2002; Venance et al. 2005; Clarke et al. 2006; Schara et al. 2008; Maggi et al. 2013). The variant was absent from 400 controls but is reported at a frequency of 0.00059 in the European American population of the Exome Sequencing Project. Cultured fibroblasts from an individual compound heterozygous for the p.Gly315Ser variant was found to have enzyme activity 20% of wild type but mRNA levels were found to be near normal (Maiti et al. 2009). Based on the evidence, the p.Gly315Ser 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. -

SELENON-related myopathy

Pathogenic:1

Feb 05, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in SELENON is predicted to replace glycine with serine at codon 315, p.(Gly315Ser). The glycine residue is highly conserved (100 vertebrates, Multiz Alignments). There is a small physicochemical difference between glycine and serine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.07% (791/1,180,030 alleles, 1 homozygote) in the European (non-Finnish) population. This variant has been detected in the homozygous and compound heterozygous state in multiple individuals with myopathy (confirmed in trans pathogenic variant in at least one individual) and segregates with disease in multiple families (PMID: 12192640, 16365872, 30932294). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.949). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PP3_Moderate. -

Eichsfeld type congenital muscular dystrophy;CN178536:Congenital myopathy 4A, autosomal dominant

Pathogenic:1

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SELENON NM_020451.2 exon 7 p.Gly315Ser (c.943G>A): (Gene also referred to as SEPN1) This variant has been reported in the literature in the homozygous or compound heterozygous state in several individuals with congenital myopathies, segregating with disease in at least 4 affected family members (Ferreiro 2002 PMID:12192640, Clarke 2006 PMID:16365872, Schara 2008 PMID:17951086, Maggi 2013 PMID:23394784). This variant is present in 0.03% (48/128676) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/1-26136244-G-A). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:4496). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

.;D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.3

.;M;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-4.4

D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.010

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.88

MVP

0.97

MPC

0.86

ClinPred

0.42

GERP RS

4.8

Varity_R

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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