ClinVar Genomic variation as it relates to human health
NM_000229.2(LCAT):c.1210A>G (p.Met404Val)
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
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NM_000229.2(LCAT):c.1210A>G (p.Met404Val)
Variation ID: 626358 Accession: VCV000626358.1
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q22.1 16: 67940017 (GRCh38) [ NCBI UCSC ] 16: 67973920 (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 Jun 17, 2019 Jun 17, 2019 Apr 29, 2019 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000229.2:c.1210A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000220.1:p.Met404Val missense NC_000016.10:g.67940017T>C NC_000016.9:g.67973920T>C NG_009778.1:g.9096A>G - Protein change
- M404V
- Other names
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- Canonical SPDI
- NC_000016.10:67940016:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Decreased function
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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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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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LCAT | - | - |
GRCh38 GRCh37 |
204 | 268 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Pathogenic (1) |
criteria provided, single submitter
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Apr 29, 2019 | RCV000782356.2 |
Submissions - Germline
Classification
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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
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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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Pathogenic
(Apr 29, 2019)
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criteria provided, single submitter
Method: research
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Norum disease
(Autosomal recessive inheritance)
Affected status: no, yes
Allele origin:
germline
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Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile
Accession: SCV000899249.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
Comment:
Methods: An adult female proband with hypoalphalipoproteinemia, corneal opacity and mild anemia, as well as her first-degree relatives, were recruited for clinical, biochemical, genetic, in-silico … (more)
Methods: An adult female proband with hypoalphalipoproteinemia, corneal opacity and mild anemia, as well as her first-degree relatives, were recruited for clinical, biochemical, genetic, in-silico and in-vitro LCAT analysis. Sequencing of exons and intron-exon boundaries was performed to identify mutations. Site-directed mutagenesis was carried out to generate plasmids containing cDNA with wild type or mutant sequences. Such expression vectors were transfected to HEK-239T cells to asses the effect of LCAT variants in expression, synthesis, secretion and enzyme activity. In silico prediction analysis and molecular modeling was also used to evaluate the effect of LCAT variants. Results: LCAT sequencing identified rare p.V333M and p.M404V missense mutations in compound heterozygous state in the proband, as well the common synonymous p.L363L variant. LCAT protein was detected in proband’s plasma, but with undetectable enzyme activity compared to control relatives. HEK-239T transfected cells with vector expression plasmids containing either p.M404V or p.V333M cDNA showed detectable LCAT protein expression both in supernatants and lysates from cultured cells, but with much lower enzyme activity compared to cells transfected with the wild-type sequence. Bioinformatic analyses also supported a causal role of such rare variations in LCAT lack of function. Conclusion: Genetic, biochemical, in vitro and in silico analyses indicate that the rare mutations p.M404V and p.V333M in LCAT gene lead to suppression of LAT enzyme activity and cause clinical features of familial LCAT deficiency. (less)
Observation 1:
Clinical Features:
Anemia (present) , Decreased HDL cholesterol concentration (present) , Corneal opacity (present)
Age: 30-39 years
Sex: female
Ethnicity/Population group: AMR
Geographic origin: Chile
Comment on evidence:
Index case (affected female) harbors LCAT p.V333M and p.M404V missense mutations in compound heterozygous state.
Method: Sanger sequencing of the complete coding sequence of LCAT gene.
Observation 2:
Age: 70-79 years
Sex: male
Ethnicity/Population group: AMR
Geographic origin: Chile
Method: Sanger sequencing of the coding region of LCAT gene
Observation 3:
Age: 70-79 years
Sex: female
Ethnicity/Population group: AMR
Geographic origin: Chile
Method: Sanger sequencing of the full coding region of LCAT gene
Observation 4:
Age: 50-59 years
Sex: male
Ethnicity/Population group: AMR
Geographic origin: Chile
Method: Sanger sequencing of the full coding region of LCAT gene
Observation 5:
Age: 50-59 years
Sex: female
Ethnicity/Population group: AMR
Geographic origin: Chile
Method: Sanger sequencing of the full coding region of LCAT gene
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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
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This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Decreased function
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Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile
Accession: SCV000899249.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Identification and functional analysis of missense mutations in the lecithin cholesterol acyltransferase gene in a Chilean patient with hypoalphalipoproteinemia. | Tobar HE | Lipids in health and disease | 2019 | PMID: 31164121 |
Text-mined citations for rs779114194 ...
HelpRecord last updated Jun 23, 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.