1-25800233-G-GGGCCGGGCCC

Variant names:

• chr1-25800233-G-GGGCCGGGCCC
• rs797044621
• NM_020451.3:c.13_22dupCGGCCGGGCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_020451.3(SELENON):​c.13_22dupCGGCCGGGCC​(p.Gln8ProfsTer78) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000213 in 799,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000082 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: SELENON NM_020451.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: -0.219

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 143 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-25800233-G-GGGCCGGGCCC is Pathogenic according to our data. Variant chr1-25800233-G-GGGCCGGGCCC is described in ClinVar as [Pathogenic]. Clinvar id is 193432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SELENON	NM_020451.3	c.13_22dupCGGCCGGGCC	p.Gln8ProfsTer78	frameshift_variant	Exon 1 of 13	ENST00000361547.7	NP_065184.2
SELENON	NM_206926.2	c.13_22dupCGGCCGGGCC	p.Gln8ProfsTer78	frameshift_variant	Exon 1 of 12		NP_996809.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SELENON	ENST00000361547.7	c.13_22dupCGGCCGGGCC	p.Gln8ProfsTer78	frameshift_variant	Exon 1 of 13	1	NM_020451.3	ENSP00000355141.2
SELENON	ENST00000374315.1	c.13_22dupCGGCCGGGCC	p.Gln8ProfsTer78	frameshift_variant	Exon 1 of 12	5		ENSP00000363434.1
SELENON	ENST00000354177.9	c.13_22dupCGGCCGGGCC	p.Gln8ProfsTer78	frameshift_variant	Exon 1 of 12	5		ENSP00000346109.5
SELENON	ENST00000494537.2	n.13_22dupCGGCCGGGCC		non_coding_transcript_exon_variant	Exon 1 of 13	3		ENSP00000508308.1

Frequencies

GnomAD3 genomes AF: 0.0000824 AC: 12 AN: 145566 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000738

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: 0.000366

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000915

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000765 AC: 5 AN: 653544 Hom.: 0 Cov.: 8 AF XY: 0.00000658 AC XY: 2 AN XY: 304040

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000714

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000502

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000824 AC: 12 AN: 145628 Hom.: 0 Cov.: 30 AF XY: 0.0000706 AC XY: 5 AN XY: 70856

Gnomad4 AFR AF: 0.0000737

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000366

Gnomad4 NFE AF: 0.0000915

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Eichsfeld type congenital muscular dystrophy Pathogenic:4

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.Gln8fs variant in SELENON has been reported in 9 individuals with SELENON-RM (PMID: 19557870, 20937510, 23394784, 11528383, 29669168, 33726816, 30921636), segregated with disease in 2 affected relatives from 1 family (PMID: 11528383), and has been identified in 0.03% (2/7988) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs970951421). Data from large population studies is insufficient to assess the frequency of this variant. Of the 9 affected individuals, 5 of those were homozygotes and 1 was a compound heterozygote that carried a reported likely pathogenic variant in trans, which increases the likelihood that the p.Gln8fs variant is pathogenic (PMID: 11528383, 19557870, 23394784, 30921636). This variant has also been reported in ClinVar (Variation ID#: 193432) and has been interpreted as pathogenic by Invitae and Eurofins NTD (LLC). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 8 and leads to a premature termination codon 78 amino acids downstream. This alteration is then 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, this variant meets criteria to be classified as pathogenic for autosomal recessive SELENON-RM. ACMG/AMP Criteria applied: PVS1, PP1, PM3_strong (Richards 2015). -

Feb 17, 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.13_22dup10 (p.Gln8ProfsX78) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 0.00012 in 24242 control chromosomes. c.13_22dup10 has been reported as homozygous and compound heterozygous genotype in the literature in multiple individuals affected with Eichsfeld Type Congenital Muscular Dystrophy (example: Moghadaszadeh_2001) and related SEPN1 myopathies (example: Park_2018, Schara_2008, Scoto_2011). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln8Profs*78) 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). This variant is present in population databases (rs797044621, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with congenital muscular dystrophy with spinal rigidity and/or congenital myopathy (PMID: 11528383, 19557870, 20937510, 23394784). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 22dup10bp. ClinVar contains an entry for this variant (Variation ID: 193432). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Apr 23, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29669168, 33726816, 35368679, 11528383, 19557870, 20937510, 24465259, 32796131, 12192640, 16498447, 37807786, 37273706, 17951086, 21670436, 23394784, 30921636, 35599849) -

Jan 15, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs797044621; hg19: chr1-26126724;