Submissions for variant NM_000235.4(LIPA):c.380G>A (p.Arg127Gln)

gnomAD frequency: 0.00009  dbSNP: rs544080483

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001093931	SCV000365996	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	RCV000265603	SCV000365997	uncertain significance	Wolman disease	2016-06-14	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000594785	SCV000707042	uncertain significance	not provided	2018-05-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001093931	SCV002780249	uncertain significance	Lysosomal acid lipase deficiency	2022-01-13	criteria provided, single submitter	clinical testing
Invitae	RCV000265603	SCV003281909	uncertain significance	Wolman disease	2022-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 127 of the LIPA protein (p.Arg127Gln). This variant is present in population databases (rs544080483, gnomAD 0.06%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 29196158, 30270055). ClinVar contains an entry for this variant (Variation ID: 301582). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LIPA protein function. Experimental studies have shown that this missense change affects LIPA function (PMID: 29196158). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.