Submissions for variant NM_020451.3(SELENON):c.746_747+36del

dbSNP: rs2047932848

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195544	SCV001365926	pathogenic	Muscular dystrophy	2020-03-27	criteria provided, single submitter	clinical testing	The c.746_747+36del deletion has been reported in the compound heterozygous state with a pathogenic variant in an individual with early-onset muscle disease and multiminicore on pathology (Scoto 2011) and in an individual with childhood-onset muscular dystrophy with adulthood-onset of respiratory issues (Broad Institute Rare Genomes Project). This variant was absent from large population studies. This variant is a deletion of 36 bases that includes the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the SELENON gene is an established disease mechanism in autosomal recessive congenital myopathy/rigid spine muscular dystrophy. In summary, this deletion meets criteria to be classified as pathogenic for autosomal recessive muscular dystrophy. ACMG/AMP Criteria applied: PVS1_Strong, PM2, PM3_Strong.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001863086	SCV002222865	pathogenic	Eichsfeld type congenital muscular dystrophy	2023-10-04	criteria provided, single submitter	clinical testing	This variant results in the deletion of part of exon 5 (c.746_747+36del) of the SELENON gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SELENON are known to be pathogenic (PMID: 21131290, 21670436). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of SELENON-related myopathy (PMID: 21670436; Invitae). ClinVar contains an entry for this variant (Variation ID: 930110). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003225961	SCV003922116	pathogenic	SELENON-related myopathy	2023-05-02	criteria provided, single submitter	curation	The heterozygous c.746_747+36del variant in SELENON was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 4492), in an individual with childhood-onset muscular dystrophy with adulthood-onset respiratory issues (Broad Institute Rare Genomes Project). Familial segregation analysis revealed that this variant was in trans with a pathogenic variant (ClinVar Variation ID: 4492). The c.746_747+36del variant in SELENON has been previously reported in one individual with SELENON-related myopathy (SELENON-RM) (PMID: 21670436). This variant is absent from population studies. This variant has also been reported in ClinVar (Variation ID: 930110) and has been interpreted as pathogenic by Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine and Invitae. The individual previously reported (PMID: 21670436) was a compound heterozygote that carried a pathogenic variant in trans (ClinVar Variation ID: 4496) and the individual identified by our study was also a compound heterozygote that carried a pathogenic variant in trans (ClinVar Variation ID: 4492), which increases the likelihood that the c.746_747+36del variant is pathogenic. This variant is a deletion of 36 bases that includes the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal 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_Strong, PM2_Supporting, PM3_Strong (Richards 2015).