ClinVar Genomic variation as it relates to human health
NM_000235.4(LIPA):c.894G>C (p.Gln298His)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000235.4(LIPA):c.894G>C (p.Gln298His)
Variation ID: 430634 Accession: VCV000430634.7
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q23.31 10: 89222511 (GRCh38) [ NCBI UCSC ] 10: 90982268 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 15, 2017 Feb 14, 2024 Oct 15, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000235.4:c.894G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000226.2:p.Gln298His missense NM_001127605.3:c.894G>C NP_001121077.1:p.Gln298His missense NM_001288979.2:c.546G>C NP_001275908.1:p.Gln182His missense NC_000010.11:g.89222511C>G NC_000010.10:g.90982268C>G NG_008194.1:g.34393G>C - Protein change
- Q298H, Q182H
- Other names
- -
- Canonical SPDI
- NC_000010.11:89222510:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
0.00060 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
LIPA | - | - |
GRCh38 GRCh37 |
633 | 664 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Likely pathogenic (2) |
criteria provided, single submitter
|
- | RCV000494734.4 | |
Pathogenic (1) |
criteria provided, single submitter
|
Oct 15, 2023 | RCV001865556.4 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Cholesteryl ester storage disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004047028.1
First in ClinVar: Oct 28, 2023 Last updated: Oct 28, 2023 |
Comment:
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). … (more)
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. (less)
Clinical Features:
Malabsorption (present) , Hepatomegaly (present) , Abnormal circulating lipid concentration (present)
|
|
Pathogenic
(Oct 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Wolman disease
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV002235665.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
|
|
Likely pathogenic
(Jul 04, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Cholesteryl ester storage disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV000583445.2
First in ClinVar: Jul 15, 2017 Last updated: Jul 15, 2017 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Visceromegaly (present) , Acholic stools (present) , Vomiting (present) , Hepatosplenomegaly (present) , Cardiac arrest (present)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Muslim/Gujarati
Geographic origin: India
Method: DNA extracted from blood was used to perform targeted gene capture using a custom capture kit. The libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. The sequences obtained were aligned to human reference genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication. Experimental observations.
|
Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Lysosomal Acid Lipase Deficiency in 23 Spanish Patients: High Frequency of the Novel c.966+2T>G Mutation in Wolman Disease. | Ruiz-Andrés C | JIMD reports | 2017 | PMID: 28220406 |
New diagnostic method for lysosomal acid lipase deficiency and the need to recognize its manifestation in infants (Wolman disease). | Gómez-Nájera M | Journal of pediatric gastroenterology and nutrition | 2015 | PMID: 24048164 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Text-mined citations for rs116928232 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.