Submissions for variant NM_020451.3(SELENON):c.827_829dup (p.Ala276_Cys277insSer)

dbSNP: rs797045950

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000192616	SCV000248845	likely pathogenic	Congenital myopathy with fiber type disproportion	2015-04-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000599220	SCV000710037	likely pathogenic	not provided	2023-12-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In-frame insertion of 1 amino acid in a non-repeat region; This variant is associated with the following publications: (PMID: 26780752, 30932294, 31069529)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002517132	SCV003760979	likely pathogenic	Eichsfeld type congenital muscular dystrophy	2023-01-24	criteria provided, single submitter	curation	The p.Ala276_Cys277insSer variant in SELENON has been reported in 2 individuals with SELENON-RM (PMID: 30932294, 26780752) and has been identified in 0.007% (2/30600) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1329981323). 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#: 212149) and has been interpreted as likely pathogenic by GeneDx and Genetic Services Laboratory (University of Chicago). Of the 2 affected individuals, both were homozygotes, which increases the likelihood that the p.Ala276_Cys277insSer variant is pathogenic (PMID: 30932294, 26780752). In vitro functional studies provide some evidence that the p.Ala276_Cys277insSer variant may impact protein function (PMID: 30932294). However, these types of assays may not accurately represent biological function. This variant is an insertion of 1 amino acid at position 276 and is not predicted to alter the protein reading-frame. This insertion is expected to impact the protein. 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: PM3, PS3_moderate, PM2_supporting, PM4_supporting (Richards 2015).
Neuberg Centre For Genomic Medicine, NCGM	RCV003338457	SCV004047880	likely pathogenic	Congenital myopathy 4A, autosomal dominant		criteria provided, single submitter	clinical testing	The inframe insertion variant c.827_829dup (p.Ala276_Cys277insSer) has been submitted to ClinVar as Likely Pathogenic. It has been reported previously using alternate nomenclature (c.829_829insTCC) in the homozygous state in an individual with significant neck extensor and flexor weakness, mild axial and limb girdle weakness, and developmental delay (Ardissone et al., 2016). This p.Ala276_Cys277insSer variant has allele frequency of 0.0008% in the gnomAD and novel (not in any individuals) in 1000 genome database . The insertion of amino acid Ser between amino acids Ala at position 276 and Cys at position 277 changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant , the molecular diagnosis is not confirmed.