Submissions for variant NM_003334.4(UBA1):c.1963C>A (p.Leu655Ile)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002423352	SCV002721462	uncertain significance	Inborn genetic diseases	2022-05-02	criteria provided, single submitter	clinical testing	The p.L655I variant (also known as c.1963C>A), located in coding exon 16 of the UBA1 gene, results from a C to A substitution at nucleotide position 1963. The leucine at codon 655 is replaced by isoleucine, an amino acid with highly similar properties. Based on data from gnomAD, the A allele has an overall frequency of 0.0005453% (1/183395) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was 0.001221% (1/81900) of European (non-Finnish) alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV003509756	SCV004323545	uncertain significance	Infantile-onset X-linked spinal muscular atrophy	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 655 of the UBA1 protein (p.Leu655Ile). This variant is present in population databases (rs782489505, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with UBA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1783480). 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 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.