PS3, PS4_Moderate, PM2, PP2, PP5
ClinVar Genomic variation as it relates to human health
NM_000039.3(APOA1):c.296T>C (p.Leu99Pro)
Germline
Classification
Help
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.
(3)
Help
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/Likely pathogenic
3
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000039.3(APOA1):c.296T>C (p.Leu99Pro)
Variation ID: 1163527 Accession: VCV001163527.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.3 11: 116836316 (GRCh38) [ NCBI UCSC ] 11: 116707032 (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 15, 2021 May 1, 2024 Jan 6, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000039.3:c.296T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000030.1:p.Leu99Pro missense NM_001318017.2:c.296T>C NP_001304946.1:p.Leu99Pro missense NM_001318018.2:c.296T>C NP_001304947.1:p.Leu99Pro missense NM_001318021.2:c.-32T>C NC_000011.10:g.116836316A>G NC_000011.9:g.116707032A>G NG_012021.1:g.6307T>C LRG_767:g.6307T>C LRG_767t1:c.296T>C LRG_767p1:p.Leu99Pro - Protein change
- L99P
- Other names
- -
- Canonical SPDI
- NC_000011.10:116836315:A:G
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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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- Links
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. |
|||
| APOA1 | - | - |
GRCh38 GRCh37 |
103 | 327 | |
| APOA1-AS | - | - | GRCh38 | - | 213 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 6, 2024 | RCV001508676.9 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 11, 2020 | RCV002439206.2 |
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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|---|---|---|---|---|---|
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Pathogenic
(Apr 23, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714992.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PS3, PS4_Moderate, PM2, PP2, PP5
Number of individuals with the variant: 1
|
|
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Pathogenic
(Jan 06, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002239472.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 99 of the APOA1 protein (p.Leu99Pro). … (more)
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 99 of the APOA1 protein (p.Leu99Pro). This variant is present in population databases (rs372520221, gnomAD 0.002%). This missense change has been observed in individual(s) with APOA1-related amyloidosis (PMID: 14986480, 15131802, 21458433, 24650283, 26193960). It has also been observed to segregate with disease in related individuals. This variant is also known as Leu75Pro. ClinVar contains an entry for this variant (Variation ID: 1163527). 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 APOA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects APOA1 function (PMID: 21296086, 24603325, 26515634). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Aug 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002746179.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.L99P variant (also known as c.296T>C), located in coding exon 3 of the APOA1 gene, results from a T to C substitution at nucleotide … (more)
The p.L99P variant (also known as c.296T>C), located in coding exon 3 of the APOA1 gene, results from a T to C substitution at nucleotide position 296. The leucine at codon 99 is replaced by proline, an amino acid with similar properties. This variant has been identified in several individuals with hepatic amyloidoses in multiple unrelated families (Coriu D et al. Amyloid, 2003 Dec;10:215-23; Obici L et al. Gastroenterology, 2004 May;126:1416-22; Eriksson M et al. J Mol Diagn, 2009 May;11:257-62). Individuals with this variant may have reduced levels of total cholesterol and high-density lipoprotein cholesterol (HDL-C) (Muiesan ML et al. Amyloid, 2015 Jul;22:187-93; Gomaraschi M et al. Clin. Chim. Acta, 2011 Jun;412:1262-5). In addition to the clinical data presented in the literature, protein aggregation and cell survival assays indicate that this alteration is functionally abnormal (Raimondi S et al. J. Mol. Biol., 2011 Apr;407:465-76; Del Giudice R et al. Cell Death Dis, 2014 Mar;5:e1097).This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
|
Comment:
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 99 of the APOA1 protein (p.Leu99Pro). This variant is present in population databases (rs372520221, gnomAD 0.002%). This missense change has been observed in individual(s) with APOA1-related amyloidosis (PMID: 14986480, 15131802, 21458433, 24650283, 26193960). It has also been observed to segregate with disease in related individuals. This variant is also known as Leu75Pro. ClinVar contains an entry for this variant (Variation ID: 1163527). 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 APOA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects APOA1 function (PMID: 21296086, 24603325, 26515634). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.L99P variant (also known as c.296T>C), located in coding exon 3 of the APOA1 gene, results from a T to C substitution at nucleotide position 296. The leucine at codon 99 is replaced by proline, an amino acid with similar properties. This variant has been identified in several individuals with hepatic amyloidoses in multiple unrelated families (Coriu D et al. Amyloid, 2003 Dec;10:215-23; Obici L et al. Gastroenterology, 2004 May;126:1416-22; Eriksson M et al. J Mol Diagn, 2009 May;11:257-62). Individuals with this variant may have reduced levels of total cholesterol and high-density lipoprotein cholesterol (HDL-C) (Muiesan ML et al. Amyloid, 2015 Jul;22:187-93; Gomaraschi M et al. Clin. Chim. Acta, 2011 Jun;412:1262-5). In addition to the clinical data presented in the literature, protein aggregation and cell survival assays indicate that this alteration is functionally abnormal (Raimondi S et al. J. Mol. Biol., 2011 Apr;407:465-76; Del Giudice R et al. Cell Death Dis, 2014 Mar;5:e1097).This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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. |
Comment:
PS3, PS4_Moderate, PM2, PP2, PP5
Comment:
This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 99 of the APOA1 protein (p.Leu99Pro). This variant is present in population databases (rs372520221, gnomAD 0.002%). This missense change has been observed in individual(s) with APOA1-related amyloidosis (PMID: 14986480, 15131802, 21458433, 24650283, 26193960). It has also been observed to segregate with disease in related individuals. This variant is also known as Leu75Pro. ClinVar contains an entry for this variant (Variation ID: 1163527). 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 APOA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects APOA1 function (PMID: 21296086, 24603325, 26515634). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.L99P variant (also known as c.296T>C), located in coding exon 3 of the APOA1 gene, results from a T to C substitution at nucleotide position 296. The leucine at codon 99 is replaced by proline, an amino acid with similar properties. This variant has been identified in several individuals with hepatic amyloidoses in multiple unrelated families (Coriu D et al. Amyloid, 2003 Dec;10:215-23; Obici L et al. Gastroenterology, 2004 May;126:1416-22; Eriksson M et al. J Mol Diagn, 2009 May;11:257-62). Individuals with this variant may have reduced levels of total cholesterol and high-density lipoprotein cholesterol (HDL-C) (Muiesan ML et al. Amyloid, 2015 Jul;22:187-93; Gomaraschi M et al. Clin. Chim. Acta, 2011 Jun;412:1262-5). In addition to the clinical data presented in the literature, protein aggregation and cell survival assays indicate that this alteration is functionally abnormal (Raimondi S et al. J. Mol. Biol., 2011 Apr;407:465-76; Del Giudice R et al. Cell Death Dis, 2014 Mar;5:e1097).This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Systemic amyloidosis: novel therapies and role of biomarkers. | Nuvolone M | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2017 | PMID: 27540044 |
| Protein conformational perturbations in hereditary amyloidosis: Differential impact of single point mutations in ApoAI amyloidogenic variants. | Del Giudice R | Biochimica et biophysica acta | 2016 | PMID: 26515634 |
| Vascular alterations in apolipoprotein A-I amyloidosis (Leu75Pro). A case-control study. | Muiesan ML | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2015 | PMID: 26193960 |
| Clinical proteome informatics workbench detects pathogenic mutations in hereditary amyloidoses. | Dasari S | Journal of proteome research | 2014 | PMID: 24650283 |
| Amyloidogenic variant of apolipoprotein A-I elicits cellular stress by attenuating the protective activity of angiogenin. | Del Giudice R | Cell death & disease | 2014 | PMID: 24603325 |
| Mutation mapping of apolipoprotein A-I structure assisted with the putative cholesterol recognition regions. | Dergunov AD | Biochimica et biophysica acta | 2013 | PMID: 23806608 |
| Effect of the amyloidogenic L75P apolipoprotein A-I variant on HDL subpopulations. | Gomaraschi M | Clinica chimica acta; international journal of clinical chemistry | 2011 | PMID: 21458433 |
| Effects of the known pathogenic mutations on the aggregation pathway of the amyloidogenic peptide of apolipoprotein A-I. | Raimondi S | Journal of molecular biology | 2011 | PMID: 21296086 |
| Hereditary apolipoprotein AI-associated amyloidosis in surgical pathology specimens: identification of three novel mutations in the APOA1 gene. | Eriksson M | The Journal of molecular diagnostics : JMD | 2009 | PMID: 19324996 |
| Liver biopsy discloses a new apolipoprotein A-I hereditary amyloidosis in several unrelated Italian families. | Obici L | Gastroenterology | 2004 | PMID: 15131802 |
| Hepatic amyloidosis resulting from deposition of the apolipoprotein A-I variant Leu75Pro. | Coriu D | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2003 | PMID: 14986480 |
| http://amyloidosismutations.com/ | - | - | - | - |
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Text-mined citations for rs372520221 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.