Submissions for variant NM_020451.3(SELENON):c.943G>A (p.Gly315Ser)

gnomAD frequency: 0.00030  dbSNP: rs121908188

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000082020	SCV000232288	pathogenic	not provided	2014-12-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000082020	SCV000322094	pathogenic	not provided	2023-09-18	criteria provided, single submitter	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)
Invitae	RCV000004753	SCV000634423	pathogenic	Eichsfeld type congenital muscular dystrophy	2024-01-16	criteria provided, single submitter	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; 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000082020	SCV000809113	pathogenic	not provided	2022-04-15	criteria provided, single submitter	clinical testing	PP3, PM2, PM3_strong, PS3_supporting, PS4
Athena Diagnostics	RCV000082020	SCV000843765	pathogenic	not provided	2015-07-08	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778235	SCV000914403	pathogenic	SEPN1-related disorder	2018-10-16	criteria provided, single submitter	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.
Undiagnosed Diseases Network, NIH	RCV000681664	SCV000930584	likely pathogenic	Eichsfeld type congenital muscular dystrophy; Congenital myopathy with fiber type disproportion	2019-05-06	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000004753	SCV000967683	pathogenic	Eichsfeld type congenital muscular dystrophy	2018-06-13	criteria provided, single submitter	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.
CeGaT Center for Human Genetics Tuebingen	RCV000082020	SCV001246685	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004754	SCV001520479	pathogenic	Congenital myopathy with fiber type disproportion	2019-12-03	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity	RCV000004753	SCV002020053	pathogenic	Eichsfeld type congenital muscular dystrophy	2023-06-01	criteria provided, single submitter	clinical testing
Centogene AG - the Rare Disease Company	RCV000004754	SCV002059710	pathogenic	Congenital myopathy with fiber type disproportion	2019-05-24	criteria provided, single submitter	clinical testing
AiLife Diagnostics, AiLife Diagnostics	RCV000082020	SCV002501873	likely pathogenic	not provided	2021-12-03	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000004753	SCV002507069	pathogenic	Eichsfeld type congenital muscular dystrophy	2022-05-04	criteria provided, single submitter	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).
Fulgent Genetics, Fulgent Genetics	RCV000681664	SCV002807135	pathogenic	Eichsfeld type congenital muscular dystrophy; Congenital myopathy with fiber type disproportion	2021-10-29	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224794	SCV003920893	likely pathogenic	Eichsfeld type congenital muscular dystrophy; Congenital myopathy 4A, autosomal dominant	2021-03-30	criteria provided, single submitter	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004753	SCV004240986	pathogenic	Eichsfeld type congenital muscular dystrophy	2023-12-12	criteria provided, single submitter	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.
Molecular Genetics, Royal Melbourne Hospital	RCV003993737	SCV004812522	pathogenic	SELENON-related myopathy	2024-02-05	criteria provided, single submitter	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.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000004753	SCV005187276	pathogenic	Eichsfeld type congenital muscular dystrophy	2024-08-12	criteria provided, single submitter	clinical testing	comp. het. with chr1:25809095-25809095 (c. 817) G>A; two affected sisters, both with both variants
OMIM	RCV000004753	SCV000024929	pathogenic	Eichsfeld type congenital muscular dystrophy	2006-03-01	no assertion criteria provided	literature only
GeneReviews	RCV000004754	SCV000058549	not provided	Congenital myopathy with fiber type disproportion		no assertion provided	literature only
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000004754	SCV000238453	pathogenic	Congenital myopathy with fiber type disproportion	2015-03-04	no assertion criteria provided	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).
Division of Human Genetics, Children's Hospital of Philadelphia	RCV000004753	SCV000238454	pathogenic	Eichsfeld type congenital muscular dystrophy	2015-03-04	no assertion criteria provided	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).