Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001865556 | SCV002235665 | pathogenic | Wolman disease | 2023-10-15 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 298 of the LIPA protein (p.Gln298His). This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with lysosomal acid lipase deficiency (PMID: 24048164, 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: 430634). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Neuberg Supratech Reference Laboratories Pvt Ltd, |
RCV000494734 | SCV004047028 | likely pathogenic | Lysosomal acid lipase deficiency | criteria provided, single submitter | clinical testing | The LIPA c.894G>C (p.Gln298His) variant has been reported in homozygous or compound heterozygous state in individuals affected with lysosomal acid lipase deficiency (Consuelo-Sánchez et al). The p.Gln298His variant is reported with the allele frequency of 0.001194% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Likely pathogenic . The amino acid Gln at position 298 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Gln298His in LIPA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely pathogenic. | |
| Foundation for Research in Genetics and Endocrinology, |
RCV000494734 | SCV000583445 | likely pathogenic | Lysosomal acid lipase deficiency | 2017-07-04 | no assertion criteria provided | clinical testing | The observed mutation is not reported in 1000 genomes and ExAC databases. However, it is reported by Gomez et al. 2015. The in silico prediction of the mutation is probably damaging by PolyPhen-2 and damaging by SIFT, LRT and MutationTaster2. The proband, born of consanguineous marriage, was presented with clinical indications of white stool, vomiting, excess crying in the night and hepatosplenomegaly from two months of age. The blood report revealed low platelet, low WBC and low hemoglobin. The proband had edema all over body. The enzyme study revealed that the proband was normal for Neiman Pick A and B disease and Gaucher disease. He died at the age of four and a half months with cardiac respiratory arrest. Mother suffered miscarriage at 1.5 months during first pregnancy. Now mother is pregnant for the third time, CVS (10 weeks) was taken to identify the same variant as found in previous child. The fetus is likely to be a carrier with Wolman disease and cholesteryl ester storage disease due to presence of heterozygous status for NM_000235.3:c.894G>C (Q298H) in exon 8 of LIPA gene. Both the parents were also studied and found to be likely carriers due to presence of the same variant. |