ClinVar Genomic variation as it relates to human health
NM_005502.4(ABCA1):c.5398A>C (p.Asn1800His)
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_005502.4(ABCA1):c.5398A>C (p.Asn1800His)
Variation ID: 364389 Accession: VCV000364389.35
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q31.1 9: 104794495 (GRCh38) [ NCBI UCSC ] 9: 107556776 (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 Dec 6, 2016 Aug 11, 2024 May 2, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_005502.4:c.5398A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_005493.2:p.Asn1800His missense NC_000009.12:g.104794495T>G NC_000009.11:g.107556776T>G NG_007981.1:g.138661A>C LRG_542:g.138661A>C LRG_542t1:c.5398A>C LRG_542p1:p.Asn1800His O95477:p.Asn1800His - Protein change
- N1800H
- Other names
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- Canonical SPDI
- NC_000009.12:104794494:T: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.
Exome Aggregation Consortium (ExAC) 0.00027
The Genome Aggregation Database (gnomAD), exomes 0.00029
Trans-Omics for Precision Medicine (TOPMed) 0.00036
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062
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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ABCA1 | - | - |
GRCh38 GRCh37 |
1160 | 1476 |
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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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Sep 2, 2023 | RCV000277325.6 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 18, 2023 | RCV001093093.21 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jul 4, 2022 | RCV001537869.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 2, 2024 | RCV002230203.2 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 22, 2023 | RCV002348116.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Dec 23, 2022 | RCV003993942.1 |
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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Pathogenic
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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ABCA1-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000476213.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
Across a selection of the available literature, the ABCA1 c.5398A>C (p.Asn1800His) variant has been identified in a total of seven individuals with ABCA1-related dyslipidemias, including … (more)
Across a selection of the available literature, the ABCA1 c.5398A>C (p.Asn1800His) variant has been identified in a total of seven individuals with ABCA1-related dyslipidemias, including in a homozygous state in one patient, in a compound heterozygous state in three patients, and in a heterozygous state in three patients (Serfaty-Lacrosniere et al. 1994; Brousseau et al. 2000; Pisciotta et al. 2004; Kiss et al. 2007; Candini et al. 2010; Sorrenson et al. 2011; Morrison et al. 2013). Frikke-Schmidt et al. (2010) stated that the p.Asn1800His variant accounted for the majority of HDL lowering variants in the Copenhagen City Heart Study and the Copenhagen General Population Study, being present in 22 and 70 heterozygotes, respectively. Control data are unavailable for this variant, which is reported at a frequency of 0.00047 in the European (non-Finnish) population of the Exome Aggregation Consortium. Brunham et al. (2006) reviewed HDL levels in 33 heterozygotes for the p.Asn1800His variant, and found that HDL levels in these cases were 56.5 percent of those in age and gender-matched controls. Frikke-Schmidt et al. (2008) found that unadjusted plasma levels of HDL cholesterol in the 22 individuals from the Copenhagen City Heart Study with the p.Asn1800His variant were reduced by 16 mg/dL when compared to controls (P<.001). Singaraja et al. (2006) demonstrated that the p.Asn1800His variant results in a defective ABCA1 protein that fails to localize to the plasma membrane and accumulates intracellularly. Based on the collective evidence, the p.Asn1800His variant is classified as pathogenic for ABCA1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(Sep 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hypoalphalipoproteinemia, primary, 1
Affected status: unknown
Allele origin:
germline
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Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001754803.1
First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021 |
Comment:
This c.5398A>C (p.Asn1800His) variant is known to have a significant impact on ABCA1 function. In-vitro functional studies suggest it prevents the migration of the resultant … (more)
This c.5398A>C (p.Asn1800His) variant is known to have a significant impact on ABCA1 function. In-vitro functional studies suggest it prevents the migration of the resultant protein to the plasma membrane, reducing the ability to efflux lipids and generate HDL cholesterol (PMID: 16873719). In the homozygous and heterozygous state, individuals with this variant had 3.4% and 56.6% of normal plasma HDL levels, respectively (PMID: 16873719, 16704350). This variant's allele frequency is 0.0006449 in the European (non-Finnish) population in gnomAD. The Asn1800 amino acid is highly conserved across species. Multiple computational tools suggest it has a deleterious effect on the gene product. This c.5398A>C (p.Asn1800His) variant in ABCA1 is therefore considered likely pathogenic. (less)
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Likely pathogenic
(Feb 15, 2021)
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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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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV002051574.2
First in ClinVar: Jan 08, 2022 Last updated: Feb 11, 2022 |
Comment:
PS3, PP3, PM2
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Likely pathogenic
(Jul 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hypoalphalipoproteinemia, primary, 1
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002581497.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3_MOD, PS4_MOD, PM2_SUP, PP3
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Number of individuals with the variant: 2
Sex: female
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Likely pathogenic
(Jun 30, 2023)
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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: SCV002050531.3
First in ClinVar: Jan 08, 2022 Last updated: Jul 08, 2023 |
Comment:
Published functional studies demonstrate that this variant damages the function of ABCA1 (Kiss et al., 2007; Singaraja et al., 2006); In silico analysis supports that … (more)
Published functional studies demonstrate that this variant damages the function of ABCA1 (Kiss et al., 2007; Singaraja et al., 2006); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34662886, 16873719, 22959828, 20800056, 21130455, 21420943, 15019541, 7945562, 17303779, 20533173, 15297675, 31980526, 28634189, 29083407, 28870971, 26073400, 26079414, 23770607, 18523221, 21575609, 20880529, 10706591, 31589614, 32041611) (less)
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Pathogenic
(Sep 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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ABCA1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004103620.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The ABCA1 c.5398A>C variant is predicted to result in the amino acid substitution p.Asn1800His. This variant has been reported in multiple patients with familial HDL … (more)
The ABCA1 c.5398A>C variant is predicted to result in the amino acid substitution p.Asn1800His. This variant has been reported in multiple patients with familial HDL deficiency or patients with Tangier disease (see for example, Table 1, Berge and Leren. 2010. PubMed ID: 20800056; Table 1, Fasano et al. 2012. PubMed ID: 22959828; Table 1, Candini et al. 2010. PubMed ID: 20880529). This variant has also been shown to segregate with HDL deficiency in multiple families (Figure 2B, Alrasadi et al. 2005. PubMed ID: 16343503; Figure 1, Pisciotta et al. 2004. PubMed ID: 15019541). An in vitro experimental study suggests this variant affects protein localization leading to intracellular accumulation (Figure 2, Singaraja et al. 2006. PubMed ID: 16873719). This variant is reported in 0.064% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-107556776-T-G). This variant is interpreted as pathogenic. (less)
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Pathogenic
(Oct 29, 2020)
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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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Revvity Omics, Revvity
Accession: SCV002017416.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 18, 2023)
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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: SCV001589908.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 1800 of the ABCA1 protein (p.Asn1800His). … (more)
This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 1800 of the ABCA1 protein (p.Asn1800His). This variant is present in population databases (rs146292819, gnomAD 0.06%). This missense change has been observed in individuals with Tangier disease or familial HDL deficiency (PMID: 10706591, 16343503, 20880529, 21575609, 22959828). This variant is also known as nt5338A>C, Asn1740His. ClinVar contains an entry for this variant (Variation ID: 364389). 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 not expected to disrupt ABCA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ABCA1 function (PMID: 16873719). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Dec 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Decreased HDL cholesterol concentration
Affected status: unknown
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004812432.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
This sequence change in ABCA1 is predicted to replace asparagine with histidine at codon 1800, p.(Asn1800His). The asparagine residue is highly conserved (98/99 vertebrates, UCSC), … (more)
This sequence change in ABCA1 is predicted to replace asparagine with histidine at codon 1800, p.(Asn1800His). The asparagine residue is highly conserved (98/99 vertebrates, UCSC), and is located in a transmembrane domain. There is a moderate physicochemical difference between asparagine and histidine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.06% (79/122,504 alleles) in the European (non-Finnish) population. The variant in the heterozygous state is significantly associated with low high-density lipoprotein cholesterol (HDL-C) lipid levels with no overt clinical manifestations (PMID: 29083407). This variant has been detected in at least five individuals with HDL-C deficiency and segregates in a single family. Of those individuals, one individual was homozygous and two were compound heterozygous for the variant and a pathogenic variant. The homozygous individual was the only proband with a clinical diagnosis of Tangier disease (PMID: 10706591, 15019541, 16343503, 20880529). At least one individual with this variant displayed impaired cellular cholesterol efflux, which is highly specific for ABCA1-related HDL-C deficiency (PMID: 10706591, 16343503). Furthermore, in vitro cellular cholesterol efflux assays, showed impaired cholesterol efflux indicating that this variant impacts protein function (PMID: 16873719, 17303779, 18523221). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM3_Strong, PS3_Supporting, PP1, PP3, PP4. (less)
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Likely pathogenic
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002652117.3
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.5398A>C (p.N1800H) alteration is located in exon 40 (coding exon 39) of the ABCA1 gene. This alteration results from a A to C substitution … (more)
The c.5398A>C (p.N1800H) alteration is located in exon 40 (coding exon 39) of the ABCA1 gene. This alteration results from a A to C substitution at nucleotide position 5398, causing the asparagine (N) at amino acid position 1800 to be replaced by a histidine (H). Based on data from gnomAD, the C allele has an overall frequency of 0.033% (87/267606) total alleles studied. The highest observed frequency was 0.065% (79/122504) of European (non-Finnish) alleles. This variant has been detected in the homozygous state in an individual reported to have Tangier disease, and has been reported to segregate with low HDL cholesterol in related heterozygotes (Serfaty-Lacrosniere, 1994; Brousseau, 2000; Pisciotta, 2004; Singaraja, 2006). This variant has been reported to co-occur with other ABCA1 variants in individuals with extremely low HDL levels, however phase was not confirmed (Candini, 2010; Sorrenson, 2011). This variant has also been reported in association with significant HDL reduction in heterozygous carriers in a population-based study, and in additional cohorts with low HDL (Alrasadi, 2006; Frikke-Schmidt, 2008; Bochem, 2013; Morrison, 2013; Dron, 2017). This amino acid position is highly conserved in available vertebrate species. In addition, several in vitro studies of patient and transfected cells exhibiting this variant demonstrated reduced cholesterol efflux (Singaraja, 2006; Kiss, 2007; Frikke-Schmidt, 2008; Sorrenson, 2011; Fasano, 2012). This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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Likely pathogenic
(May 02, 2024)
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criteria provided, single submitter
Method: clinical testing
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Familial hypoalphalipoproteinemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002511718.2
First in ClinVar: May 16, 2022 Last updated: Aug 11, 2024 |
Comment:
Variant summary: ABCA1 c.5398A>C (p.Asn1800His) results in a conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein … (more)
Variant summary: ABCA1 c.5398A>C (p.Asn1800His) results in a conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 240978 control chromosomes, predominantly at a frequency of 0.00057 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 57-fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA1 causing Familial Hypoalphalipoproteinemia phenotype (1e-05). However, c.5398A>C has been reported in the literature in multiple individuals affected with Familial Hypoalphalipoproteinemia, including one homozygote (Brousseau_2000), compound heterozygotes (e.g. Pisciotta_2004, Alrasadi_2006, Candini_2010) and several heterozygotes (e.g. Alrasadi_2006, Berge_2010, Fasano_2012). These data indicate that the variant is very likely to be associated with disease. Publications report experimental evidence evaluating an impact on protein function. The variant protein resulted in a loss of cholesterol efflux activity and impaired localization at the plasma membrane (Singaraja_2006, Kiss_2007). The following publications have been ascertained in the context of this evaluation (PMID: 20880529, 16343503, 20800056, 10706591, 22959828, 15019541, 16873719, 17303779). ClinVar contains an entry for this variant (Variation ID: 364389). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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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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Exome chip meta-analysis identifies novel loci and East Asian-specific coding variants that contribute to lipid levels and coronary artery disease. | Lu X | Nature genetics | 2017 | PMID: 29083407 |
Polygenic determinants in extremes of high-density lipoprotein cholesterol. | Dron JS | Journal of lipid research | 2017 | PMID: 28870971 |
Whole-genome sequence-based analysis of high-density lipoprotein cholesterol. | Morrison AC | Nature genetics | 2013 | PMID: 23770607 |
ABCA1 mutation carriers with low high-density lipoprotein cholesterol are characterized by a larger atherosclerotic burden. | Bochem AE | European heart journal | 2013 | PMID: 23136402 |
Novel mutations of ABCA1 transporter in patients with Tangier disease and familial HDL deficiency. | Fasano T | Molecular genetics and metabolism | 2012 | PMID: 22959828 |
An ABCA1 truncation shows no dominant negative effect in a familial hypoalphalipoproteinemia pedigree with three ABCA1 mutations. | Sorrenson B | Biochemical and biophysical research communications | 2011 | PMID: 21575609 |
Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol. | Candini C | Atherosclerosis | 2010 | PMID: 20880529 |
Mutations in APOA-I and ABCA1 in Norwegians with low levels of HDL cholesterol. | Berge KE | Clinica chimica acta; international journal of clinical chemistry | 2010 | PMID: 20800056 |
Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease. | Frikke-Schmidt R | JAMA | 2008 | PMID: 18523221 |
Genetic etiology of isolated low HDL syndrome: incidence and heterogeneity of efflux defects. | Kiss RS | Arteriosclerosis, thrombosis, and vascular biology | 2007 | PMID: 17303779 |
Specific mutations in ABCA1 have discrete effects on ABCA1 function and lipid phenotypes both in vivo and in vitro. | Singaraja RR | Circulation research | 2006 | PMID: 16873719 |
Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis. | Brunham LR | Annual review of nutrition | 2006 | PMID: 16704350 |
Functional mutations of the ABCA1 gene in subjects of French-Canadian descent with HDL deficiency. | Alrasadi K | Atherosclerosis | 2006 | PMID: 16343503 |
Familial HDL deficiency due to ABCA1 gene mutations with or without other genetic lipoprotein disorders. | Pisciotta L | Atherosclerosis | 2004 | PMID: 15019541 |
Novel mutations in the gene encoding ATP-binding cassette 1 in four tangier disease kindreds. | Brousseau ME | Journal of lipid research | 2000 | PMID: 10706591 |
Homozygous Tangier disease and cardiovascular disease. | Serfaty-Lacrosniere C | Atherosclerosis | 1994 | PMID: 7945562 |
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Text-mined citations for rs146292819 ...
HelpRecord last updated Sep 17, 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.