Submissions for variant NM_020451.3(SELENON):c.103G>C (p.Gly35Arg)

gnomAD frequency: 0.00020  dbSNP: rs398124359

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723675	SCV000113943	uncertain significance	not provided	2013-06-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000723675	SCV000617112	uncertain significance	not provided	2017-07-11	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the SEPN1 gene. The G35R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. No data are available from control populations to assess the frequency of this variant. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant
Labcorp Genetics (formerly Invitae), Labcorp	RCV000558595	SCV000634394	likely benign	Eichsfeld type congenital muscular dystrophy	2024-01-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001097299	SCV001253563	uncertain significance	SEPN1-related disorder	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
CeGaT Center for Human Genetics Tuebingen	RCV000723675	SCV001500350	uncertain significance	not provided	2022-04-01	criteria provided, single submitter	clinical testing	SELENON: PP3
Baylor Genetics	RCV001329140	SCV001520476	uncertain significance	Congenital myopathy with fiber type disproportion	2019-12-13	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000723675	SCV002541919	uncertain significance	not provided	2021-11-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000558595	SCV003819303	uncertain significance	Eichsfeld type congenital muscular dystrophy	2023-11-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162515	SCV003879430	uncertain significance	Inborn genetic diseases	2023-02-16	criteria provided, single submitter	clinical testing	The c.103G>C (p.G35R) alteration is located in exon 1 (coding exon 1) of the SEPN1 gene. This alteration results from a G to C substitution at nucleotide position 103, causing the glycine (G) at amino acid position 35 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003398680	SCV004122970	uncertain significance	not specified	2023-10-16	criteria provided, single submitter	clinical testing	Variant summary: SELENON c.103G>C (p.Gly35Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 4190 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.103G>C in individuals affected with Eichsfeld Type Congenital Muscular Dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=7) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.