Submissions for variant NM_000235.4(LIPA):c.253C>A (p.Gln85Lys)

dbSNP: rs797045094

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Alexion Pharmaceuticals, Inc	RCV000857278	SCV000999870	likely pathogenic	Lysosomal acid lipase deficiency	2019-06-01	criteria provided, single submitter	research
Invitae	RCV001858539	SCV002264213	pathogenic	Wolman disease	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 85 of the LIPA protein (p.Gln85Lys). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with lysosomal acid lipase deficiency (PMID: 25624737, 31182375; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 695063). 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 expected to disrupt LIPA protein function. Experimental studies have shown that this missense change affects LIPA function (PMID: 29196158, 31131398, 31180157). This variant disrupts the p.Gln85 amino acid residue in LIPA. Other variant(s) that disrupt this residue have been observed in individuals with LIPA-related conditions (PMID: 9684740), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001858539	SCV002500382	pathogenic	Wolman disease	2022-03-02	criteria provided, single submitter	clinical testing	Variant summary: LIPA c.253C>A (p.Gln85Lys) results in a conservative amino acid change located in the Alpha/beta hydrolase fold-1 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251360 control chromosomes. c.253C>A has been reported in the literature in individuals affected with Lysosomal Acid Lipase Deficiency in the homozygous and compound heterozygous state (Consuelo-Sanchez_2019, Cappuccio_2019). These data indicate that the variant is likely to be associated with disease. A functional study reports the variant the result in <10% enzyme activity in transiently transfected cell lysates (Vinje_2018). In addition, a different variant affecting the same codon (Q85R) has been reported in association with cholesterol ester storage disease (HGMD). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.