VCV000009483.4 - ClinVar

NM_005502.4(ABCA1):c.4429T>C (p.Cys1477Arg)

Germline

Classification

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Likely pathogenic

1 out of 3 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005502.4(ABCA1):c.4429T>C (p.Cys1477Arg)

Variation ID: 9483 Accession: VCV000009483.4

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q31.1 9: 104806276 (GRCh38) [ NCBI UCSC ] 9: 107568557 (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	Feb 19, 2018	Nov 15, 2025	May 8, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_005502.4:c.4429T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005493.2:p.Cys1477Arg	missense
NM_005502.3:c.4429T>C
NC_000009.12:g.104806276A>G
NC_000009.11:g.107568557A>G
NG_007981.1:g.126880T>C
LRG_542:g.126880T>C
LRG_542t1:c.4429T>C	LRG_542p1:p.Cys1477Arg
	O95477:p.Cys1477Arg

... more HGVS ... less HGVS

Protein change

C1477R

Other names

C1417R

Canonical SPDI

NC_000009.12:104806275:A:G

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA120477 UniProtKB: O95477#VAR_009153 OMIM: 600046.0001 dbSNP: rs137854494 VarSome

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
Gene	OMIM	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.
ABCA1		-	-	GRCh38 GRCh37	1507	1879

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.
Tangier disease	Pathogenic (1)	no assertion criteria provided	Aug 1, 1999	RCV000010091.5
ABCA1-related disorder	Pathogenic (1)	no assertion criteria provided	Dec 31, 2023	RCV004532322.2
not provided	Likely pathogenic (1)	criteria provided, single submitter	May 8, 2025	RCV006250236.1

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.	Expand all rows Collapse all rows 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 (May 08, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV007099373.1 First in ClinVar: Nov 15, 2025 Last updated: Nov 15, 2025	Comment: show Published functional studies demonstrate a damaging effect leading to low ApoA-I binding and significantly reduced phosphocholine and cholesterol efflux (PMID: 16873719, 24097981, 14701824); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing.; This variant is associated with the following publications: (PMID: 24097981, 37889183, 16873719, 14701824, 20880529, 10431236, 18776170, 14746569, 38052254, 31366948) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Aug 01, 1999) N Not contributing to aggregate classification	no assertion criteria provided	TANGIER DISEASE	OMIM Accession: SCV000030312.4 First in ClinVar: Apr 04, 2013 Last updated: Feb 19, 2018	Publications: PubMed (1) PubMed: 10431236 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In the proband with Tangier disease (TGD; 205400) in a Dutch family, Brooks-Wilson et al. (1999) found compound heterozygosity for mutations in the ABC1 gene. … (more) In the proband with Tangier disease (TGD; 205400) in a Dutch family, Brooks-Wilson et al. (1999) found compound heterozygosity for mutations in the ABC1 gene. One mutation was a T-to-C transition at nucleotide 4369 in exon 30, predicted to result in a cys1417-to-arg (C1417R) substitution. The other mutation was a G-to-C transversion in the splice donor site of exon 24 (600046.0002), predicted to cause alternative splicing and deletion of a significant part of the transcript. (less)

Pathogenic (Dec 31, 2023) N Not contributing to aggregate classification	no assertion criteria provided	ABCA1-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004720329.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: show The ABCA1 c.4429T>C variant is predicted to result in the amino acid substitution p.Cys1477Arg. This variant has been reported in the heterozygous state in multiple individuals with high-density lipoprotein deficiency (reported as p.Cys1417Arg in Figure 3, Brooks-Wilson et al. 1999. PubMed ID: 10431236; Table 1, Candini et al. 2010. PubMed ID: 20880529) and it has also been reported in the compound heterozygous state in an individual with Tangier disease (Table 1, Haidar et al. 2003. PubMed ID: 14701824). This variant has not been reported in a large population database, indicating this variant is rare. In vitro experimental studies suggest this variant impacts ApoA1 binding, phosphocholine transport, and cholesterol transport (Figure 3, Singaraja et al. 2006. PubMed ID: 16873719; Quazi et al. 2013. PubMed ID: 24097981). An alternate nucleotide change at the same amino acid (p.Cys1477Phe), has been reported in multiple individuals with high-density lipoprotein deficiency (Table 3, Cohen et al. 2004. PubMed ID: 15297675; Table 1, Berge et al. 2010. PubMed ID: 20800056). The c.4429T>C (p.Cys1477Arg) variant is interpreted as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

Published functional studies demonstrate a damaging effect leading to low ApoA-I binding and significantly reduced phosphocholine and cholesterol efflux (PMID: 16873719, 24097981, 14701824); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis suggests this variant may impact gene splicing.; This variant is associated with the following publications: (PMID: 24097981, 37889183, 16873719, 14701824, 20880529, 10431236, 18776170, 14746569, 38052254, 31366948)

Comment:

The ABCA1 c.4429T>C variant is predicted to result in the amino acid substitution p.Cys1477Arg. This variant has been reported in the heterozygous state in multiple individuals with high-density lipoprotein deficiency (reported as p.Cys1417Arg in Figure 3, Brooks-Wilson et al. 1999. PubMed ID: 10431236; Table 1, Candini et al. 2010. PubMed ID: 20880529) and it has also been reported in the compound heterozygous state in an individual with Tangier disease (Table 1, Haidar et al. 2003. PubMed ID: 14701824). This variant has not been reported in a large population database, indicating this variant is rare. In vitro experimental studies suggest this variant impacts ApoA1 binding, phosphocholine transport, and cholesterol transport (Figure 3, Singaraja et al. 2006. PubMed ID: 16873719; Quazi et al. 2013. PubMed ID: 24097981). An alternate nucleotide change at the same amino acid (p.Cys1477Phe), has been reported in multiple individuals with high-density lipoprotein deficiency (Table 3, Cohen et al. 2004. PubMed ID: 15297675; Table 1, Berge et al. 2010. PubMed ID: 20800056). The c.4429T>C (p.Cys1477Arg) variant is interpreted as pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.	Brooks-Wilson A	Nature genetics	1999	PMID: 10431236

Text-mined citations for rs137854494 ...

These 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 Nov 15, 2025