Description
Variant summary: LIPA c.894G>A (p.Gln298Gln) alters a conserved nucleotide in a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site and two predict the variant weakens a 5' donor site. Multiple publications report experimental evidence that this variant disrupts the normal splicing sequence, resulting in alternate splicing and the skipping of exon 8 (e.g. Aslandis_1996, Pagani_1998). Although this has been shown to produce an inactive protein, the variant produces a small proportion (3-5%) of mRNA transcripts which are spliced correctly, resulting in a residual level of enzyme activity (e.g. Aslandis_1996, Pagani_1998). The variant allele was found at a frequency of 0.00091 in 251194 control chromosomes (gnomAD), predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database. c.894G>A has been reported in the literature in the homozygous and compound heterozygous state in many individuals affected with Lysosomal Acid Lipase Deficiency and has been noted as one of the most common pathogenic variants associated with this disorder (e.g.Fasano_2012, Lipinski_2018, Consuelo-Sanchez_2019, Mayanskiy_2019). These data indicate that the variant is very likely to be associated with disease. Thirteen assessments for this variant have been submitted to ClinVar after 2014. Twelve submitters classified the variant as pathogenic and one classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
