ClinVar Genomic variation as it relates to human health

Variant summary: The variant involves the deletion of exons 1-15 in the AASS gene. A presumed nomenclature of c.(?_-105)_(1655+1_1656-1)del has been designated for the purposes of this classification. The exact breakpoint at the 5' end of this variant is unknown, therefore this deletion may extend upstream of the annotated region of this gene. Although the exact breakpoints of this deletion are not known, it is predicted to remove the initiation codon and result in an absence of protein or a truncation of the encoded protein due to translation initiation at a downstream site. An alternative downstream in-frame start codon (Met573) is located in exon 16 of the encoded protein. An activation of this potential downstream translation initiation site would result in a shortened protein missing the first 572 amino acids from the protein sequence, resulting in a large deletion in the AASS gene, a known mechanism of disease. Multiple variants (including missense, nonsense, and frameshift) located upstream of this alternate initiation codon have been reported as pathogenic/disease-associated in ClinVar, HGMD and LOVD. The variant was absent in 21694 control chromosomes (gnomAD Structural Variants dataset). To our knowledge, no occurrence of c.(?_-105)_(1655+1_1656-1)del in individuals affected with Hyperlysinemia and no experimental evidence demonstrating its impact on protein function have been reported. The following publication was ascertained in the context of this evaluation (PMID: 36983702). One submitter has reported clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as benign, however without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.