NM_020451.3(SELENON):c.1469G>A (p.Trp490Ter) AND Eichsfeld type congenital muscular dystrophy

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 3, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000535222.12

Allele description [Variation Report for NM_020451.3(SELENON):c.1469G>A (p.Trp490Ter)]

NM_020451.3(SELENON):c.1469G>A (p.Trp490Ter)

Gene:

SELENON:selenoprotein N [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.11

Genomic location:

Preferred name:

NM_020451.3(SELENON):c.1469G>A (p.Trp490Ter)

Other names:

NM_020451.3(SELENON):c.1469G>A; p.Trp490Ter

HGVS:

NC_000001.11:g.25813962G>A
NG_009930.1:g.18787G>A
NM_020451.3:c.1469G>AMANE SELECT
NM_206926.2:c.1367G>A
NP_065184.2:p.Trp490Ter
NP_996809.1:p.Trp456Ter
LRG_857t1:c.1469G>A
LRG_857:g.18787G>A
LRG_857p1:p.Trp490Ter
NC_000001.10:g.26140453G>A
NM_020451.2:c.1469G>A

Protein change:

W456*

Links:

dbSNP: rs960468382

NCBI 1000 Genomes Browser:

rs960468382

Molecular consequence:

NM_020451.3:c.1469G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_206926.2:c.1367G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Eichsfeld type congenital muscular dystrophy (CMYO3)
Synonyms:: MYOPATHY, SEPN1-RELATED; Rigid spine muscular dystrophy 1; CONGENITAL MYOPATHY 3 WITH RIGID SPINE
Identifiers:: MONDO: MONDO:0011271; MedGen: C0410180; OMIM: 602771

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000634401	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 3, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21131290, 21670436, 28492532
SCV003761284	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 24, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000634401

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 3, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV003761284

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 24, 2023)

germline

curation

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Satellite cell loss and impaired muscle regeneration in selenoprotein N deficiency.

Castets P, Bertrand AT, Beuvin M, Ferry A, Le Grand F, Castets M, Chazot G, Rederstorff M, Krol A, Lescure A, Romero NB, Guicheney P, Allamand V.

Hum Mol Genet. 2011 Feb 15;20(4):694-704. doi: 10.1093/hmg/ddq515. Epub 2010 Dec 2.

PubMed [citation]

PMID:: 21131290

Scoto M, Cirak S, Mein R, Feng L, Manzur AY, Robb S, Childs AM, Quinlivan RM, Roper H, Jones DH, Longman C, Chow G, Pane M, Main M, Hanna MG, Bushby K, Sewry C, Abbs S, Mercuri E, Muntoni F.

Neurology. 2011 Jun 14;76(24):2073-8. doi: 10.1212/WNL.0b013e31821f467c.

PubMed [citation]

PMID:: 21670436

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000634401.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 461630). This variant has not been reported in the literature in individuals affected with SELENON-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.009%). This sequence change creates a premature translational stop signal (p.Trp490*) in the SELENON gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SELENON are known to be pathogenic (PMID: 21131290, 21670436).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003761284.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The p.Trp490Ter variant in SELENON has not been previously reported in the literature in individuals with SELENON-RM but has been identified in 0.009% (3/34522) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs960468382). 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#: 461630) and has been interpreted as pathogenic by Invitae, Eurofins NTD (LLC), and PerkinElmer Genomics. This nonsense variant leads to a premature termination codon at position 490 which is predicted to lead to a truncated or absent protein. Loss of function of the SELENON gene is an established disease mechanism in autosomal recessive SELENON-RM. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive SELENON-RM. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine