Submissions for variant NM_000235.4(LIPA):c.754A>T (p.Ile252Leu)

gnomAD frequency: 0.00140  dbSNP: rs147493628

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000887810	SCV000365982	uncertain significance	Lysosomal acid lipase deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000287212	SCV000365983	uncertain significance	Wolman disease	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001705448	SCV000572892	likely benign	not provided	2021-02-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29196158)
Eurofins Ntd Llc (ga)	RCV000478562	SCV000702213	likely benign	not specified	2017-04-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000287212	SCV001031396	likely benign	Wolman disease	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002392837	SCV002675182	uncertain significance	Cardiovascular phenotype	2023-03-22	criteria provided, single submitter	clinical testing	The p.I252L variant (also known as c.754A>T), located in coding exon 6 of the LIPA gene, results from an A to T substitution at nucleotide position 754. The isoleucine at codon 252 is replaced by leucine, an amino acid with highly similar properties. This variant was reported as heterozygous in one individual from a hypercholesterolemia cohort, but clinical details were not provided (Vinje T et al. Mol. Genet. Metab., 2018 02;123:169-176). This amino acid position is not well 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.
Natera, Inc.	RCV000887810	SCV001456941	likely benign	Lysosomal acid lipase deficiency	2020-04-11	no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000478562	SCV001917983	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001705448	SCV001964416	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544508	SCV004768979	likely benign	LIPA-related disorder	2021-04-18	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).