Submissions for variant NM_000235.4(LIPA):c.1052ACG[1] (p.Asp352del)

dbSNP: rs767207643

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001206098	SCV001377389	pathogenic	Wolman disease	2023-11-06	criteria provided, single submitter	clinical testing	This variant, c.1055_1057del, results in the deletion of 1 amino acid(s) of the LIPA protein (p.Asp352del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs767207643, gnomAD 0.0009%). This variant has been observed in individual(s) with cholesteryl ester storage disorder and/or lysosomal acid lipase deficiency (LAL) (PMID: 27624512, 28220406; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 937141). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001836138	SCV003921864	likely pathogenic	Lysosomal acid lipase deficiency		criteria provided, single submitter	clinical testing	- In-frame insertion/deletion in a non-repetitive region that has high conservation. - Variant is present in gnomAD (v2) - This variant has limited previous evidence of pathogenicity in unrelated individuals. This variant has been described along with a second variant in the literature in two individuals with lysosomal acid lipase deficiency (LAL-D) or cholesteryl ester storage disorder (CESD), although the phasing of the variants was not confirmed in either case (PMID: 27624512, 28220406). This variant was also reported in a poster abstract in an individual with late-onset LAL-D (Antwi et al 2021), and has been reported as a VUS in ClinVar. Additional information: - Loss of function is a known mechanism of disease in this gene and is associated with cholesteryl ester storage disease (CEST) and Wolman disease (MIM#278000). - This gene is associated with autosomal recessive disease. - This variant is heterozygous. - Variant is located in the annotated AB hydrolase-1 domain (UniProt). - No comparable in-frame deletion variants have previous evidence for pathogenicity. - No published segregation evidence has been identified for this variant. - No published functional evidence has been identified for this variant. - This variant has been shown to be paternally inherited (by trio analysis).
Natera, Inc.	RCV001836138	SCV002088936	uncertain significance	Lysosomal acid lipase deficiency	2020-10-05	no assertion criteria provided	clinical testing