The E2096K variant in the ABCA4 gene has been published previously in association with Stargardt disease (Lewis et al., 1999; Shroyer et al., 2001; Utz et al., 2013). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). E2096K is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, E2096K has been shown to significantly reduce ATPase activity of the ABCA4 protein (Sun et al., 2000). In summary, we consider this variant to be pathogenic
ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.6286G>A (p.Glu2096Lys)
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.
(5)
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.
Conflicting classifications of pathogenicity
Pathogenic(3); Uncertain significance(1)
Pathogenic(3); Uncertain significance(1)
5
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000350.3(ABCA4):c.6286G>A (p.Glu2096Lys)
Variation ID: 99445 Accession: VCV000099445.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p22.1 1: 94001102 (GRCh38) [ NCBI UCSC ] 1: 94466658 (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 20, 2014 Feb 14, 2024 Jun 3, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000350.3:c.6286G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000341.2:p.Glu2096Lys missense NM_001425324.1:c.6064G>A NP_001412253.1:p.Glu2022Lys missense NC_000001.11:g.94001102C>T NC_000001.10:g.94466658C>T NG_009073.1:g.125048G>A NG_009073.2:g.125046G>A P78363:p.Glu2096Lys - Protein change
- E2096K, E2022K
- Other names
- -
- Canonical SPDI
- NC_000001.11:94001101:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- 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. |
|||
| ABCA4 | - | - |
GRCh38 GRCh37 |
3754 | 4108 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Jun 3, 2023 | RCV000085804.11 |
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
(Sep 02, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000344272.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Pathogenic
(Oct 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000616627.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The E2096K variant in the ABCA4 gene has been published previously in association with Stargardt disease (Lewis et al., 1999; Shroyer et al., 2001; Utz … (more)
The E2096K variant in the ABCA4 gene has been published previously in association with Stargardt disease (Lewis et al., 1999; Shroyer et al., 2001; Utz et al., 2013). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). E2096K is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, E2096K has been shown to significantly reduce ATPase activity of the ABCA4 protein (Sun et al., 2000). In summary, we consider this variant to be pathogenic (less)
|
|
|
Pathogenic
(Jun 19, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Accession: SCV001448852.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Number of individuals with the variant: 1
Clinical Features:
Cognitive impairment (present) , Intellectual disability, borderline (present) , Accelerated skeletal maturation (present) , Tall stature (present) , Broad nasal tip (present) , Agenesis of … (more)
Cognitive impairment (present) , Intellectual disability, borderline (present) , Accelerated skeletal maturation (present) , Tall stature (present) , Broad nasal tip (present) , Agenesis of permanent teeth (present) , Cone/cone-rod dystrophy (present) , Esotropia (present) , Amblyopia (present) , Acanthosis nigricans (present) , Toe walking (present) , Motor delay (present) , Chronic constipation (present) , Abnormality of the liver (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Abnormality of the axillary hair (present) , Nevus (present) , Sensory impairment (present) , Abnormality of the kidney (present) (less)
Sex: female
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Pathogenic
(Jun 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004292358.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). Advanced modeling … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). 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 ABCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 99445). This missense change has been observed in individual(s) with Stargardt disease (PMID: 11726554, 29925512, 33691693). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs61750646, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2096 of the ABCA4 protein (p.Glu2096Lys). (less)
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|
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not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
Retina International
Accession: SCV000117947.1
First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014
Comment:
http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_ABCR:c.6286G>A
|
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). 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 ABCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 99445). This missense change has been observed in individual(s) with Stargardt disease (PMID: 11726554, 29925512, 33691693). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs61750646, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2096 of the ABCA4 protein (p.Glu2096Lys).
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:
The E2096K variant in the ABCA4 gene has been published previously in association with Stargardt disease (Lewis et al., 1999; Shroyer et al., 2001; Utz et al., 2013). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). E2096K is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, E2096K has been shown to significantly reduce ATPase activity of the ABCA4 protein (Sun et al., 2000). In summary, we consider this variant to be pathogenic
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087). 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 ABCA4 protein function. ClinVar contains an entry for this variant (Variation ID: 99445). This missense change has been observed in individual(s) with Stargardt disease (PMID: 11726554, 29925512, 33691693). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs61750646, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2096 of the ABCA4 protein (p.Glu2096Lys).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Whole-exome sequencing in 168 Korean patients with inherited retinal degeneration. | Ma DJ | BMC medical genomics | 2021 | PMID: 33691693 |
| Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8. | Fujinami K | The British journal of ophthalmology | 2019 | PMID: 29925512 |
| Cosegregation and functional analysis of mutant ABCR (ABCA4) alleles in families that manifest both Stargardt disease and age-related macular degeneration. | Shroyer NF | Human molecular genetics | 2001 | PMID: 11726554 |
| Biochemical defects in ABCR protein variants associated with human retinopathies. | Sun H | Nature genetics | 2000 | PMID: 11017087 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4 | - | - | - | - |
Text-mined citations for rs61750646 ...
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.