ClinVar Genomic variation as it relates to human health
NM_000236.3(LIPC):c.1214C>T (p.Thr405Met)
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.
Pathogenic(1); Uncertain significance(3); Benign(2); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000236.3(LIPC):c.1214C>T (p.Thr405Met)
Variation ID: 14451 Accession: VCV000014451.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q21.3 15: 58563549 (GRCh38) [ NCBI UCSC ] 15: 58855748 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 May 12, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000236.3:c.1214C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000227.2:p.Thr405Met missense NC_000015.10:g.58563549C>T NC_000015.9:g.58855748C>T NG_011465.2:g.136574C>T P11150:p.Thr405Met - Protein change
- T405M
- Other names
- T383M
- Canonical SPDI
- NC_000015.10:58563548:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00120 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00109
1000 Genomes Project 0.00120
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00139
Trans-Omics for Precision Medicine (TOPMed) 0.00148
Exome Aggregation Consortium (ExAC) 0.00276
The Genome Aggregation Database (gnomAD), exomes 0.00293
The Genome Aggregation Database (gnomAD) 0.00299
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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LIPC | - | - |
GRCh38 GRCh37 |
259 | 282 |
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. |
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Uncertain significance (3) |
criteria provided, single submitter
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Apr 27, 2017 | RCV000015536.33 | |
Benign/Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV001610291.12 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 24, 2020 | RCV001449771.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 24, 2022 | RCV003227602.3 | |
Pathogenic (1) |
criteria provided, single submitter
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May 4, 2022 | RCV002247345.3 |
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. |
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Uncertain significance
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Hyperlipidemia due to hepatic triglyceride lipase deficiency
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001280120.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Jun 24, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001653046.1
First in ClinVar: May 29, 2021 Last updated: May 29, 2021 |
Comment:
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr405Met variant in LIPC (also reported as p.Thr383Met in the literature) has been identified in the … (more)
Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr405Met variant in LIPC (also reported as p.Thr383Met in the literature) has been identified in the compound heterozygous state in at least 2 individuals with hepatic lipase deficiency and segregated with disease in 5 affected relatives from 2 families (Hegele 1991 PMID: 1883393, Hegele 1991 PMID: 1671786, Ruel 2003 PMID: 12777476 ). This variant has also been identified in the heterozygous state in 3 individuals with biochemical features consistent with hepatic lipase deficiency (Knudsen 1996 PMID: 8732782, Motazacker 2013 PMID: 23685560, Geller 2018 PMID: 30333156). Additionally, this variant has been reported in ClinVar (Variation ID # 14451) and has been identified in 1.5% (388/25112) of Finnish chromosomes, including 3 homozygotes, and 0.3% (460/129166) of European chromosomes, including 2 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant impacts protein function (Knudsen 1996 PMID: 8732782, Durstenfeld 1994 PMID: 8123642); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain as it is unclear what clinical effect of the biochemical change in lipid levels has on people with hepatic lipase deficiency, particularly on how they affect the risk of atherosclerosis in some individuals and not in others and whether that risk is greater than individuals in the general population (Brunzell 2011 PMID: 21986251, Kobayashi 2015 PMID: 25995285). ACMG/AMP Criteria applied:PP1_Strong, PM3, PS3_Supporting. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Type 2 diabetes mellitus
Affected status: unknown
Allele origin:
germline
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Mendelics
Accession: SCV002517566.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
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Benign
(Jan 12, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV003252591.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
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Likely benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004699317.3
First in ClinVar: Mar 10, 2024 Last updated: May 12, 2024 |
Comment:
LIPC: BS1
Number of individuals with the variant: 1
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Benign
(Nov 09, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001833408.1
First in ClinVar: Sep 12, 2021 Last updated: Sep 12, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 32041611, 31589614, 31980526, 30333156, 28870971, 1671786, 24082139, 24497850, 20981092, 8732782, 1883393, 23685560, 8123642)
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Uncertain significance
(Feb 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Type 1 diabetes mellitus 2
High density lipoprotein cholesterol level quantitative trait locus 12 Hyperlipidemia due to hepatic triglyceride lipase deficiency
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Accession: SCV003925206.1
First in ClinVar: May 20, 2023 Last updated: May 20, 2023 |
Observation 1:
Clinical Features:
Hyperlipidemia (present)
Secondary finding: no
Observation 2:
Clinical Features:
Hyperlipidemia (present) , Hepatic steatosis (present) , Diabetes mellitus (present)
Secondary finding: no
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Likely pathogenic
(Jan 06, 2020)
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no assertion criteria provided
Method: curation
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Hepatic lipase deficiency
Affected status: unknown
Allele origin:
germline
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Reproductive Health Research and Development, BGI Genomics
Accession: SCV001142450.1
First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020 |
Comment:
NM_000236.2:c.1214C>T in the LIPC gene has an allele frequency of 0.015 in European(Finnish) subpopulation in the gnomAD database.Functional studies demonstrate that p.Thr405Met has reduced enzymatic … (more)
NM_000236.2:c.1214C>T in the LIPC gene has an allele frequency of 0.015 in European(Finnish) subpopulation in the gnomAD database.Functional studies demonstrate that p.Thr405Met has reduced enzymatic activity (PMID: 1883393). It was detected in multiple individuals with autosomal recessive Hepatic lipase deficiency, compound heterozygous with c.1214C>T (p.Thr405Met) (PMID: 1883393).The patient's phenotype is highly specific for LIPC gene (PMID: 1671786). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM3; PP4. (less)
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Pathogenic
(Aug 01, 2003)
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no assertion criteria provided
Method: literature only
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HEPATIC LIPASE DEFICIENCY
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035801.2
First in ClinVar: Apr 04, 2013 Last updated: Jul 07, 2021 |
Comment on evidence:
In 6 individuals with complete HL deficiency (614025) from 2 unrelated families, 1 of French descent living in Quebec and a second of Irish and … (more)
In 6 individuals with complete HL deficiency (614025) from 2 unrelated families, 1 of French descent living in Quebec and a second of Irish and English descent living in Ontario, Hegele et al. (1991) found a 1221C-T transition in exon 8 of the LIPC gene that caused a thr383-to-met (T383M) substitution in the mature enzyme. Hegele et al. (1991) identified a second mutation in the LIPC gene (S267F; 151670.0002) in the 3 affected individuals of the Ontario family, and Ruel et al. (2003) identified a second mutation in LIPC (A174T; 151670.0006) in affected members of the Quebec family. In a Finnish man with HL deficiency, Knudsen et al. (1996) identified compound heterozygous mutations in the LIPC gene: T383M and a leu334-to-phe (L334F; 151670.0007) substitution in exon 7. The mutations, which were found by a combination of single-strand confirmation polymorphism analysis and whole-exome sequencing of the LIPC gene, segregated with the disorder in the family. The L334F mutation was identified in 8 of 170 alleles tested in the Finnish population. Transfection experiments in COS-1 cells showed that the T383M mutation resulted in reduced hepatic lipase expression and function, and that the L334F mutation resulted in normal hepatic lipase expression but reduced enzymatic function. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics, Academic Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001919380.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021 |
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001970264.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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 |
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Genetic and secondary causes of severe HDL deficiency and cardiovascular disease. | Geller AS | Journal of lipid research | 2018 | PMID: 30333156 |
Polygenic determinants in extremes of high-density lipoprotein cholesterol. | Dron JS | Journal of lipid research | 2017 | PMID: 28870971 |
Lipoprotein lipase and atherosclerosis. | Kobayashi J | Annals of clinical biochemistry | 2015 | PMID: 25995285 |
Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk. | Holmen OL | Nature genetics | 2014 | PMID: 24633158 |
Re-sequencing expands our understanding of the phenotypic impact of variants at GWAS loci. | Service SK | PLoS genetics | 2014 | PMID: 24497850 |
Evidence of a polygenic origin of extreme high-density lipoprotein cholesterol levels. | Motazacker MM | Arteriosclerosis, thrombosis, and vascular biology | 2013 | PMID: 23685560 |
The effect of hepatic lipase on coronary artery disease in humans is influenced by the underlying lipoprotein phenotype. | Brunzell JD | Biochimica et biophysica acta | 2012 | PMID: 21986251 |
Characterization of a novel mutation causing hepatic lipase deficiency among French Canadians. | Ruel IL | Journal of lipid research | 2003 | PMID: 12777476 |
A compound heterozygote for hepatic lipase gene mutations Leu334-->Phe and Thr383-->Met: correlation between hepatic lipase activity and phenotypic expression. | Knudsen P | Journal of lipid research | 1996 | PMID: 8732782 |
Molecular characterization of human hepatic lipase deficiency. In vitro expression of two naturally occurring mutations. | Durstenfeld A | Arteriosclerosis and thrombosis : a journal of vascular biology | 1994 | PMID: 8123642 |
Compound heterozygosity for mutant hepatic lipase in familial hepatic lipase deficiency. | Hegele RA | Biochemical and biophysical research communications | 1991 | PMID: 1883393 |
A hepatic lipase gene mutation associated with heritable lipolytic deficiency. | Hegele RA | The Journal of clinical endocrinology and metabolism | 1991 | PMID: 1671786 |
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Text-mined citations for rs113298164 ...
HelpRecord last updated May 12, 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.