rs121908188

chr1-25809753-G-Achr1-25809753-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 O:1
• Conservation: PhyloP100: 8.12

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]

ACMG classification

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/exons	MANE	UniProt
SELENON	NM_020451.3	c.943G>A	p.Gly315Ser	missense_variant	7/13	ENST00000361547.7
SELENON	NM_206926.2	c.841G>A	p.Gly281Ser	missense_variant	6/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SELENON	ENST00000361547.7	c.943G>A	p.Gly315Ser	missense_variant	7/13	1	NM_020451.3
SELENON	ENST00000374315.1	c.841G>A	p.Gly281Ser	missense_variant	6/12	5		P1
SELENON	ENST00000354177.9	c.772G>A	p.Gly258Ser	missense_variant	6/12	5
SELENON	ENST00000494537.2	c.841G>A	p.Gly281Ser	missense_variant, NMD_transcript_variant	6/13	3

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152104 Hom.: 0 Cov.: 33

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: 44 AN: 249510 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135396

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.: 1 Cov.: 32 AF XY: 0.000490 AC XY: 356 AN XY: 727218

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: 44 AN: 152104 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74288

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.: 0

Bravo AF: 0.000287

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000233 AC: 1

ESP6500EA AF: 0.000588 AC: 5

ExAC AF: 0.000173 AC: 21

EpiCase AF: 0.000654

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 12, 2023	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. -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Mar 04, 2015	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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 13, 2018	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. -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	May 04, 2022	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	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; 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. ClinVar contains an entry for this variant (Variation ID: 4496). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SELENON protein function. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 24, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 08, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 15, 2022	PP3, PM2, PM3_strong, PS3_supporting, PS4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Dec 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2019	- -

Congenital myopathy with fiber type disproportion Pathogenic:3 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 03, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Mar 04, 2015	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	May 24, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Eichsfeld type congenital muscular dystrophy;C0546264:Congenital myopathy with fiber type disproportion Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 29, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	May 06, 2019	- -

SEPN1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 16, 2018

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

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Feb 05, 2024

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

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Mar 30, 2021

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	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.77	T
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	T
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

Other links and lift over

dbSNP: rs121908188; hg19: chr1-26136244;