Submissions for variant NM_003334.4(UBA1):c.1486G>A (p.Glu496Lys)

gnomAD frequency: 0.00033  dbSNP: rs140950898

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000346007	SCV000482380	benign	Infantile-onset X-linked spinal muscular atrophy	2018-01-12	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.
GeneDx	RCV000523614	SCV000619997	uncertain significance	not provided	2017-08-16	criteria provided, single submitter	clinical testing	The E496K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E496K variant is observed in 13/47,965 (0.03%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position where amino acids with similar properties to Glutamic acid are tolerated across species. However, 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000346007	SCV000639852	benign	Infantile-onset X-linked spinal muscular atrophy	2024-10-28	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000523614	SCV001146577	likely benign	not provided	2019-05-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002392932	SCV002700464	likely benign	Inborn genetic diseases	2020-03-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Clinical Genetics, Academic Medical Center	RCV000523614	SCV001918372	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000523614	SCV001972612	likely benign	not provided		no assertion criteria provided	clinical testing