Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory of Inherited Metabolic Diseases, |
RCV001075889 | SCV001241530 | likely pathogenic | Lysosomal acid lipase deficiency | 2019-12-19 | criteria provided, single submitter | research | ACMG Guidelines, 2015 criteria: PS3, PM2, PP4 |
Invitae | RCV001862637 | SCV002267464 | pathogenic | Wolman disease | 2023-07-17 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with lysosomal acid lipase deficiency (PMID: 31230978). This sequence change affects codon 200 of the LIPA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the LIPA protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 21 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 867231). Studies have shown that this variant results in the activation of a cryptic splice site in exon 6 (PMID: 31230978). This variant disrupts a region of the LIPA protein in which other variant(s) (p.Leu200Pro) have been determined to be pathogenic (PMID: 7499245, 8146180, 8598644, 8617513, 31230978). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001862637 | SCV004020506 | likely pathogenic | Wolman disease | 2023-06-02 | criteria provided, single submitter | clinical testing | Variant summary: LIPA c.600G>A alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in a 63 bp deletion (Bychkov_2019). The variant was absent in 251462 control chromosomes. c.600G>A has been reported in the literature in one homozygous individual affected with Lysosomal Acid Lipase Deficiency (Bychkov_2019). Enzymatic analysis of this individual indicates a severe decrease in Lyposomal Acid Lipase activity both in leukocytes and dried blood spots. The following publication have been ascertained in the context of this evaluation (PMID: 31230978). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=1), likely pathogenic (n=1) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
OMIM | RCV001449673 | SCV001652922 | pathogenic | Cholesteryl ester storage disease | 2023-06-02 | no assertion criteria provided | literature only |