Submissions for variant NM_020451.3(SELENON):c.1112G>A (p.Gly371Asp)

dbSNP: rs745886248

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000713178	SCV000843763	uncertain significance	not provided	2017-10-04	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000791287	SCV000930586	likely pathogenic	Eichsfeld type congenital muscular dystrophy; Congenital myopathy with fiber type disproportion	2019-05-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000713178	SCV001246686	uncertain significance	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Invitae	RCV001861985	SCV002204502	uncertain significance	Eichsfeld type congenital muscular dystrophy	2022-09-21	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 371 of the SELENON protein (p.Gly371Asp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SELENON-related conditions. ClinVar contains an entry for this variant (Variation ID: 586530). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001861985	SCV003761133	uncertain significance	Eichsfeld type congenital muscular dystrophy	2023-01-24	criteria provided, single submitter	curation	The p.Gly371Asp variant in SELENON has not been previously reported in the literature in individuals with SELENON-RM but has been identified in 0.003% (1/32300) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs745886248). 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#: 586530) and has been interpreted as a variant of uncertain significance by Athena Diagnostics Inc and CeGaT Praxis fuer Humangenetik Tuebingen and likely pathogenic by the Undiagnosed Diseases Network (NIH). 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, the clinical significance of the p.Gly371Asp variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting (Richards 2015).
GeneDx	RCV000713178	SCV003924616	uncertain significance	not provided	2023-05-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Institute of Human Genetics, University Hospital Muenster	RCV003985417	SCV004801692	uncertain significance	See cases	2023-07-20	criteria provided, single submitter	clinical testing	ACMG categories: PM2,BP1