Submissions for variant NM_003919.3(SGCE):c.391A>G (p.Ile131Val)

gnomAD frequency: 0.00015  dbSNP: rs370609227

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000416039	SCV000493494	uncertain significance	not provided	2017-04-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000416039	SCV000701959	uncertain significance	not provided	2016-10-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000689645	SCV000817308	uncertain significance	Myoclonic dystonia 11	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 131 of the SGCE protein (p.Ile131Val). This variant is present in population databases (rs370609227, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SGCE-related conditions. ClinVar contains an entry for this variant (Variation ID: 374642). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Illumina Laboratory Services, Illumina	RCV000689645	SCV001327355	benign	Myoclonic dystonia 11	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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469145	SCV002766237	uncertain significance	not specified	2024-04-17	criteria provided, single submitter	clinical testing	Variant summary: SGCE c.391A>G (p.Ile131Val) results in a conservative amino acid change located in the dystroglycan-type cadherin-like domain (IPR006644) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant is located near a canonical splice site and therefore may affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5' donor site. Two predict the variant strengthens a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00018 in 247766 control chromosomes, predominantly at a frequency of 0.00037 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is higher than would be expected for a rare autosomal dominant disorder, suggesting the variant may be benign. However it should be noted that in SGCE-related Myoclonic Dystonia, penetrance is determined by parental origin of the altered allele due to maternal imprinting, therefore a pathogenic variant on the maternally-derived SGCE allele typically does not result in the disease phenotype (Raymond_2003, Gene Reviews), making it difficult to interpret whether the frequency of the c.391A>G variant in the control population allows for any conclusion about variant significance. To our knowledge, no occurrence of c.391A>G in individuals affected with Myoclonic Dystonia 11 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 374642). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000689645	SCV003819903	uncertain significance	Myoclonic dystonia 11	2021-12-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003362776	SCV004053006	uncertain significance	Inborn genetic diseases	2023-08-10	criteria provided, single submitter	clinical testing	The c.391A>G (p.I131V) alteration is located in exon 4 (coding exon 4) of the SGCE gene. This alteration results from a A to G substitution at nucleotide position 391, causing the isoleucine (I) at amino acid position 131 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000416039	SCV001798903	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000416039	SCV001966902	uncertain significance	not provided		no assertion criteria provided	clinical testing