The c.5714+5G>A variant in ABCA4 is one of the most common variants in ABCA4 in patients with autosomal recessive Stargardt disease, accounting for up to 16% of disease-causing variants in this gene (Cremers 1998, River 2000, Smaragda 2018, Birtel 2018). It has also been identified in 71/129064 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 99403). This variant is located in the 5' splice region, and in vitro functional studies support an impact on protein function (Rivera 2000, Sangermano 2018). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Stargardt disease. ACMG/AMP Criteria applied: PM3_VeryStrong, PVS1_Strong, PP1.
ClinVar Genomic variation as it relates to human health
NM_000350.3(ABCA4):c.5714+5G>A
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.
(33)
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
33
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
This variant is part of a Haplotype
- Identifiers
-
NM_000350.3(ABCA4):c.5714+5G>A
Variation ID: 99403 Accession: VCV000099403.72
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 1p22.1 1: 94010795 (GRCh38) [ NCBI UCSC ] 1: 94476351 (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 Dec 7, 2024 Oct 8, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000350.3:c.5714+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000001.11:g.94010795C>T NC_000001.10:g.94476351C>T NG_009073.1:g.115355G>A NG_009073.2:g.115353G>A - Protein change
- -
- Other names
-
IVS40DS, G-A, +5
- Canonical SPDI
- NC_000001.11:94010794:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
sequence_variant_affecting_splicing; Sequence Ontology [ SO:1000071]
-
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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00031
Exome Aggregation Consortium (ExAC) 0.00035
The Genome Aggregation Database (gnomAD) 0.00036
Trans-Omics for Precision Medicine (TOPMed) 0.00038
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00100
- 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 |
3770 | 4126 | |
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 (9) |
criteria provided, multiple submitters, no conflicts
|
Jul 1, 2024 | RCV000085757.53 | |
| Likely pathogenic (2) |
criteria provided, single submitter
|
- | RCV000210303.14 | |
| Pathogenic/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Oct 8, 2024 | RCV000210321.22 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Sep 7, 2018 | RCV000778997.13 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 4, 2024 | RCV001074898.11 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 4, 2019 | RCV001196124.11 | |
| Pathogenic (2) |
no assertion criteria provided
|
Jul 23, 2015 | RCV000332324.14 | |
| Pathogenic (4) |
criteria provided, single submitter
|
May 8, 2019 | RCV000515694.16 | |
| not provided (1) |
no classification provided
|
- | RCV000845081.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 4, 2022 | RCV002498458.8 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 11, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000341399.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Zygosity: Single Heterozygote
Sex: mixed
|
|
|
Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001135329.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Pathogenic
(May 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Stargardt disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001365627.1
First in ClinVar: Jul 06, 2020 Last updated: Jul 06, 2020 |
Comment:
The c.5714+5G>A variant in ABCA4 is one of the most common variants in ABCA4 in patients with autosomal recessive Stargardt disease, accounting for up to … (more)
The c.5714+5G>A variant in ABCA4 is one of the most common variants in ABCA4 in patients with autosomal recessive Stargardt disease, accounting for up to 16% of disease-causing variants in this gene (Cremers 1998, River 2000, Smaragda 2018, Birtel 2018). It has also been identified in 71/129064 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 99403). This variant is located in the 5' splice region, and in vitro functional studies support an impact on protein function (Rivera 2000, Sangermano 2018). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Stargardt disease. ACMG/AMP Criteria applied: PM3_VeryStrong, PVS1_Strong, PP1. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447613.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Macular degeneration (present)
Sex: male
|
|
|
Pathogenic
(Jun 04, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Age related macular degeneration 2
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001366611.2
First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3.
|
|
|
Likely pathogenic
(Jan 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Institute of Medical Molecular Genetics, University of Zurich
Accession: SCV001548065.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Method: long-range PCR
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Retinitis pigmentosa 19
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760047.1
First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021 |
|
|
|
Pathogenic
(Jan 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Age related macular degeneration 2
Severe early-childhood-onset retinal dystrophy Retinitis pigmentosa 19 Cone-rod dystrophy 3
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002809894.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Aug 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002505619.3
First in ClinVar: Apr 30, 2022 Last updated: Sep 09, 2023 |
Comment:
Criteria applied: PM3_VSTR,PS4,PS3_MOD,PS1_SUP,PM2_SUP,PP1
Clinical Features:
Visual field defect (present) , Macular dystrophy (present) , Abnormality of vision (present)
Sex: male
|
|
|
Pathogenic
(Mar 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002018137.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001217350.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change falls in intron 40 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. … (more)
This sequence change falls in intron 40 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs61751407, gnomAD 0.05%). This variant has been observed in individuals with autosomal recessive Stargardt disease and cone-rod dystrophy (PMID: 9466990, 10413692, 19074458). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99403). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV005087245.2
First in ClinVar: Jul 23, 2024 Last updated: Nov 24, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease 1 (MIM#248200) and other inherited retinal diseases (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31522899). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. A mini gene assay showed that this variant led to two products; a correctly spliced one and one with exon 40 skipped (PMID: 29162642). (SP) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (highest allele count: 672 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals with Stargardt (PMID: 10958763) and classified as pathogenic by multiple diagnostic laboratories in ClinVar. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Likely pathogenic
(Oct 04, 2024)
|
criteria provided, single submitter
Method: research
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital
Accession: SCV005420687.1
First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024 |
Comment:
PS3,PM3(strong),PM2,PP3
|
|
|
Pathogenic
(Jan 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV000281936.2
First in ClinVar: Dec 07, 2016 Last updated: Dec 07, 2016 |
Indication for testing: Stargardt disease 1
Zygosity: Homozygote, Single Heterozygote
|
|
|
Pathogenic
(Sep 07, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
ABCA4-Related Disorders
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000915438.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
Across a selection of the available literature, the ABCA4 c.5714+5G>A variant, also referred to as IVS40+5G>A, has been identified in 26 individuals with Stargardt disease, … (more)
Across a selection of the available literature, the ABCA4 c.5714+5G>A variant, also referred to as IVS40+5G>A, has been identified in 26 individuals with Stargardt disease, including in one homozygote, 20 compound heterozygotes, and five heterozygotes in whom a second variant was not identified, and in six compound heterozygotes with cone-rod dystrophy (Cremers et al. 1998; Rivera et al. 2000; Gerth et al. 2002; Hargitai et al. 2005; Hwang et al. 2009; Cideciyan et al. 2009). The variant was also found in four unaffected family members in a heterozygous state. The variant was absent from 320 control individuals, but is reported at a frequency of 0.00151 in the European American population of the Exome Sequencing Project. RT-PCR analysis of transformed COS-7 cells revealed that the c.5714+5G>A variant generates both a correctly spliced and an incorrectly spliced product, suggesting aberrant splicing with a possibility of some residual activity of the ABCA4 protein (Rivera et al. 2000). Based on the collective evidence, the c.5714+5G>A variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
|
|
Pathogenic
(Aug 16, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Blueprint Genetics
Accession: SCV001240502.1
First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020
Comment:
My Retina Tracker patient
|
|
|
|
Pathogenic
(Apr 08, 2021)
|
criteria provided, single submitter
Method: research
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Ocular Genomics Institute, Massachusetts Eye and Ear
Accession: SCV001573567.1
First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Comment:
The ABCA4 c.5714+5G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more)
The ABCA4 c.5714+5G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1. Based on this evidence we have classified this variant as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000321355.12
First in ClinVar: Oct 09, 2016 Last updated: Sep 16, 2024 |
Comment:
Minigene splice assays in HEK293 cells demonstrate that the c.5714+5G>A variant construct results in exon 40 skipping, which was confirmed by cDNA sequencing (PMID: 29162642, … (more)
Minigene splice assays in HEK293 cells demonstrate that the c.5714+5G>A variant construct results in exon 40 skipping, which was confirmed by cDNA sequencing (PMID: 29162642, 28714225); This variant is associated with the following publications: (PMID: 11702214, 28365912, 30903310, 30093795, 31429209, 32531858, 33706644, 34758253, 31456290, 10413692, 24265693, 25066811, 22328824, 17982420, 9466990, 21911583, 11328725, 19074458, 28341476, 26872967, 28118664, 28838317, 28044389, 29555955, 30771335, 30670881, 29925512, 31589614, 32619608, 34327195, 33302505, 32783370, 32815999, 32467599, 31980526, 32581362, 35836572, 35119454, 28714225, 35260635, 36209838, 37217489, 36460718, 29162642) (less)
|
|
|
Pathogenic
(Jul 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001247603.26
First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024 |
Comment:
ABCA4: PM3:Very Strong, PM2, PS3:Supporting
Number of individuals with the variant: 22
|
|
|
Pathogenic
(Jan 23, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Retinitis pigmentosa 19
Affected status: yes
Allele origin:
germline
|
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals
Accession: SCV000259077.1
First in ClinVar: Mar 25, 2016 Last updated: Mar 25, 2016 |
|
|
|
Pathogenic
(Jan 22, 2015)
|
no assertion criteria provided
Method: clinical testing
|
Severe early-childhood-onset retinal dystrophy
Affected status: yes
Allele origin:
germline
|
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals
Accession: SCV000259089.1
First in ClinVar: Mar 25, 2016 Last updated: Mar 25, 2016 |
|
|
|
Pathogenic
(Jul 23, 2015)
|
no assertion criteria provided
Method: research
|
Cone-rod dystrophy 3
Affected status: unknown
Allele origin:
germline
|
Division of Human Genetics, Children's Hospital of Philadelphia
Study: CSER-PediSeq
Accession: SCV000536750.1 First in ClinVar: Apr 22, 2017 Last updated: Apr 22, 2017 |
|
|
|
Likely pathogenic
(Jan 01, 2015)
|
no assertion criteria provided
Method: research
|
None
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV000599001.1
First in ClinVar: Dec 07, 2016 Last updated: Dec 07, 2016 |
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: European
|
|
|
Likely pathogenic
(Apr 01, 2018)
|
no assertion criteria provided
Method: research
|
Stargardt disease
Affected status: yes
Allele origin:
unknown
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Study: VeluxRD
Accession: SCV000926481.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023 |
|
|
|
Pathogenic
(Jul 01, 2008)
|
no assertion criteria provided
Method: literature only
|
CONE-ROD DYSTROPHY 3
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000028553.4
First in ClinVar: Apr 04, 2013 Last updated: Jul 06, 2020 |
Comment on evidence:
Cremers et al. (1998) presented evidence that a 5-prime splice site mutation in intron 40 (IVS40+5G-A) in compound heterozygous state with the IVS30+1G-T mutation (601691.0009) … (more)
Cremers et al. (1998) presented evidence that a 5-prime splice site mutation in intron 40 (IVS40+5G-A) in compound heterozygous state with the IVS30+1G-T mutation (601691.0009) in the ABCR gene can result in cone-rod dystrophy (CORD3; 604116). In 3 patients with autosomal recessive CORD and diffuse pigmentary degenerative changes, Fishman et al. (2003) identified the IVS40+5G-A mutation. In a 30-year-old man with cone dystrophy, Kitiratschky et al. (2008) identified compound heterozygosity for the IVS40 5714+5G-A splice site mutation and an L1940P substitution (601690.0033) in the ABCA4 gene. The patient, who had onset of disease at 7 years of age, had normal color vision, normal glare sensitivity and night vision, atrophy of the RPE and choroid as well as RPE clumping in the area of the macula, central scotoma, and a reduced cone but normal rod electroretinogram. Both mutations were also identified in his affected sister, and their unaffected mother was heterozygous for the L1940P mutation; information was unavailable on their father. In an asymptomatic man with STGD1-like flecks in his fundus, Lee et al. (2019) identified heterozygosity for the IVS40+5G-A splicing mutation in the ABCA4 gene. His daughter, who exhibited severe Stargardt disease, was heterozygous for the ABCA4 splicing mutation as well as a missense mutation in the PROM1 gene (R134C; 604365.0007), inherited from her less severely affected mother. The authors stated that they could not unequivocally attribute the father's phenotype to the ABCA4 mutation; they concluded that monoallelic variation is not sufficient for disease, but that certain mutations may cause mild late-onset manifestation of STGD1 subphenotypes. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955151.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Severe early-childhood-onset retinal dystrophy
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana
Accession: SCV005049255.1
First in ClinVar: Jun 09, 2024 Last updated: Jun 09, 2024 |
|
|
|
Pathogenic
(Sep 18, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ABCA4-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005351186.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The ABCA4 c.5714+5G>A variant is predicted to interfere with splicing. This variant (also known as IVS40+5G>A) has been reported in individuals with inherited retinal disease … (more)
The ABCA4 c.5714+5G>A variant is predicted to interfere with splicing. This variant (also known as IVS40+5G>A) has been reported in individuals with inherited retinal disease (see for examples Cremers et al. 1998. PubMed ID: 9466990; Klevering et al. 2004. PubMed ID: 15494742; Birtel et al. 2018. PubMed ID: 29555955). This variant is predicted to disrupt normal splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751), and functional analysis by RT-PCR revealed that this variant indeed produces both normal and abnormal splicing products (Rivera et al. 2000. PubMed ID: 10958763). This variant is reported in 0.055% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99403/). We classify this variant as pathogenic. (less)
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Pathogenic
(May 09, 2017)
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no assertion criteria provided
Method: research
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Stargardt disease
Affected status: yes
Allele origin:
germline
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Rui Chen Lab, Baylor College of Medicine
Accession: SCV000579418.1
First in ClinVar: Dec 03, 2017 Last updated: Dec 03, 2017
Comment:
An in vitrominigene system was used to confirm that the variant disrupts splicing
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Pathogenic
(Jun 23, 2019)
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no assertion criteria provided
Method: research
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Stargardt disease
Affected status: yes
Allele origin:
inherited
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Sharon lab, Hadassah-Hebrew University Medical Center
Accession: SCV001160825.1
First in ClinVar: Feb 17, 2020 Last updated: Feb 17, 2020 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001966459.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
unknown
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Retina International
Accession: SCV000117898.1
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.5714%2B5G>A
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not provided
(-)
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no classification provided
Method: phenotyping only
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Stargardt disease
Cone-rod dystrophy
Affected status: unknown
Allele origin:
paternal
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GenomeConnect, ClinGen
Accession: SCV000986928.1
First in ClinVar: Aug 31, 2019 Last updated: Aug 31, 2019 |
Comment:
Variant interpretted as pathogenic and reported on 07/26/2017 by GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from … (more)
Variant interpretted as pathogenic and reported on 07/26/2017 by GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less)
Clinical Features:
Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Abnormal delivery (present) , Prenatal maternal abnormality (present) , Abnormality of the placenta … (more)
Abnormality of the amniotic fluid (present) , Decreased fetal movement (present) , Abnormal delivery (present) , Prenatal maternal abnormality (present) , Abnormality of the placenta (present) , Maternal teratogenic exposure (present) , Premature birth (present) , Abnormality of the umbilical cord (present) , Overgrowth (present) , Obesity (present) , Tall stature (present) , Abnormality of the ear (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Hypertonia (present) , Generalized hypotonia (present) , Memory impairment (present) , Anxiety (present) , Depressivity (present) , Short attention span (present) , Joint hypermobility (present) , Abnormality of muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Asthma (present) , Abnormal pattern of respiration (present) , Abnormality of the male genitalia (present) , Recurrent infections (present) , Misalignment of teeth (present) (less)
Age: 20-29 years
Sex: male
Testing laboratory: Invitae
Date variant was reported to submitter: 2017-07-26
Testing laboratory interpretation: Pathogenic
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Comment:
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3.
Comment:
Criteria applied: PM3_VSTR,PS4,PS3_MOD,PS1_SUP,PM2_SUP,PP1
Comment:
This sequence change falls in intron 40 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs61751407, gnomAD 0.05%). This variant has been observed in individuals with autosomal recessive Stargardt disease and cone-rod dystrophy (PMID: 9466990, 10413692, 19074458). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99403). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease 1 (MIM#248200) and other inherited retinal diseases (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31522899). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. A mini gene assay showed that this variant led to two products; a correctly spliced one and one with exon 40 skipped (PMID: 29162642). (SP) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (highest allele count: 672 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals with Stargardt (PMID: 10958763) and classified as pathogenic by multiple diagnostic laboratories in ClinVar. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
PS3,PM3(strong),PM2,PP3
Comment:
Across a selection of the available literature, the ABCA4 c.5714+5G>A variant, also referred to as IVS40+5G>A, has been identified in 26 individuals with Stargardt disease, including in one homozygote, 20 compound heterozygotes, and five heterozygotes in whom a second variant was not identified, and in six compound heterozygotes with cone-rod dystrophy (Cremers et al. 1998; Rivera et al. 2000; Gerth et al. 2002; Hargitai et al. 2005; Hwang et al. 2009; Cideciyan et al. 2009). The variant was also found in four unaffected family members in a heterozygous state. The variant was absent from 320 control individuals, but is reported at a frequency of 0.00151 in the European American population of the Exome Sequencing Project. RT-PCR analysis of transformed COS-7 cells revealed that the c.5714+5G>A variant generates both a correctly spliced and an incorrectly spliced product, suggesting aberrant splicing with a possibility of some residual activity of the ABCA4 protein (Rivera et al. 2000). Based on the collective evidence, the c.5714+5G>A variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The ABCA4 c.5714+5G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1. Based on this evidence we have classified this variant as Pathogenic.
Comment:
Minigene splice assays in HEK293 cells demonstrate that the c.5714+5G>A variant construct results in exon 40 skipping, which was confirmed by cDNA sequencing (PMID: 29162642, 28714225); This variant is associated with the following publications: (PMID: 11702214, 28365912, 30903310, 30093795, 31429209, 32531858, 33706644, 34758253, 31456290, 10413692, 24265693, 25066811, 22328824, 17982420, 9466990, 21911583, 11328725, 19074458, 28341476, 26872967, 28118664, 28838317, 28044389, 29555955, 30771335, 30670881, 29925512, 31589614, 32619608, 34327195, 33302505, 32783370, 32815999, 32467599, 31980526, 32581362, 35836572, 35119454, 28714225, 35260635, 36209838, 37217489, 36460718, 29162642)
Comment:
ABCA4: PM3:Very Strong, PM2, PS3:Supporting
Comment:
The ABCA4 c.5714+5G>A variant is predicted to interfere with splicing. This variant (also known as IVS40+5G>A) has been reported in individuals with inherited retinal disease (see for examples Cremers et al. 1998. PubMed ID: 9466990; Klevering et al. 2004. PubMed ID: 15494742; Birtel et al. 2018. PubMed ID: 29555955). This variant is predicted to disrupt normal splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751), and functional analysis by RT-PCR revealed that this variant indeed produces both normal and abnormal splicing products (Rivera et al. 2000. PubMed ID: 10958763). This variant is reported in 0.055% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99403/). We classify this variant as pathogenic.
Comment:
Variant interpretted as pathogenic and reported on 07/26/2017 by GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
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
Help
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
Help
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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sequence_variant_affecting_splicing
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Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Accession: SCV000281936.2
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sequence_variant_affecting_splicing
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Rui Chen Lab, Baylor College of Medicine
Accession: SCV000579418.1
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Comment:
The c.5714+5G>A variant in ABCA4 is one of the most common variants in ABCA4 in patients with autosomal recessive Stargardt disease, accounting for up to 16% of disease-causing variants in this gene (Cremers 1998, River 2000, Smaragda 2018, Birtel 2018). It has also been identified in 71/129064 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 99403). This variant is located in the 5' splice region, and in vitro functional studies support an impact on protein function (Rivera 2000, Sangermano 2018). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Stargardt disease. ACMG/AMP Criteria applied: PM3_VeryStrong, PVS1_Strong, PP1.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM3,PP3.
Comment:
Criteria applied: PM3_VSTR,PS4,PS3_MOD,PS1_SUP,PM2_SUP,PP1
Comment:
This sequence change falls in intron 40 of the ABCA4 gene. It does not directly change the encoded amino acid sequence of the ABCA4 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs61751407, gnomAD 0.05%). This variant has been observed in individuals with autosomal recessive Stargardt disease and cone-rod dystrophy (PMID: 9466990, 10413692, 19074458). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99403). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease 1 (MIM#248200) and other inherited retinal diseases (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31522899). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. A mini gene assay showed that this variant led to two products; a correctly spliced one and one with exon 40 skipped (PMID: 29162642). (SP) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (highest allele count: 672 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in individuals with Stargardt (PMID: 10958763) and classified as pathogenic by multiple diagnostic laboratories in ClinVar. (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
PS3,PM3(strong),PM2,PP3
Comment:
Across a selection of the available literature, the ABCA4 c.5714+5G>A variant, also referred to as IVS40+5G>A, has been identified in 26 individuals with Stargardt disease, including in one homozygote, 20 compound heterozygotes, and five heterozygotes in whom a second variant was not identified, and in six compound heterozygotes with cone-rod dystrophy (Cremers et al. 1998; Rivera et al. 2000; Gerth et al. 2002; Hargitai et al. 2005; Hwang et al. 2009; Cideciyan et al. 2009). The variant was also found in four unaffected family members in a heterozygous state. The variant was absent from 320 control individuals, but is reported at a frequency of 0.00151 in the European American population of the Exome Sequencing Project. RT-PCR analysis of transformed COS-7 cells revealed that the c.5714+5G>A variant generates both a correctly spliced and an incorrectly spliced product, suggesting aberrant splicing with a possibility of some residual activity of the ABCA4 protein (Rivera et al. 2000). Based on the collective evidence, the c.5714+5G>A variant is classified as pathogenic for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
The ABCA4 c.5714+5G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PM3, PP1. Based on this evidence we have classified this variant as Pathogenic.
Comment:
Minigene splice assays in HEK293 cells demonstrate that the c.5714+5G>A variant construct results in exon 40 skipping, which was confirmed by cDNA sequencing (PMID: 29162642, 28714225); This variant is associated with the following publications: (PMID: 11702214, 28365912, 30903310, 30093795, 31429209, 32531858, 33706644, 34758253, 31456290, 10413692, 24265693, 25066811, 22328824, 17982420, 9466990, 21911583, 11328725, 19074458, 28341476, 26872967, 28118664, 28838317, 28044389, 29555955, 30771335, 30670881, 29925512, 31589614, 32619608, 34327195, 33302505, 32783370, 32815999, 32467599, 31980526, 32581362, 35836572, 35119454, 28714225, 35260635, 36209838, 37217489, 36460718, 29162642)
Comment:
ABCA4: PM3:Very Strong, PM2, PS3:Supporting
Comment:
The ABCA4 c.5714+5G>A variant is predicted to interfere with splicing. This variant (also known as IVS40+5G>A) has been reported in individuals with inherited retinal disease (see for examples Cremers et al. 1998. PubMed ID: 9466990; Klevering et al. 2004. PubMed ID: 15494742; Birtel et al. 2018. PubMed ID: 29555955). This variant is predicted to disrupt normal splicing (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751), and functional analysis by RT-PCR revealed that this variant indeed produces both normal and abnormal splicing products (Rivera et al. 2000. PubMed ID: 10958763). This variant is reported in 0.055% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/99403/). We classify this variant as pathogenic.
Comment:
Variant interpretted as pathogenic and reported on 07/26/2017 by GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Stargardt Disease Due to an Intronic Mutation in the ABCA4: A Case Report. | Lugo-Merly A | International medical case reports journal | 2022 | PMID: 36471740 |
| Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases. | Maggi J | International journal of molecular sciences | 2021 | PMID: 33546218 |
| Modification of the PROM1 disease phenotype by a mutation in ABCA4. | Lee W | Ophthalmic genetics | 2019 | PMID: 31576780 |
| Highly Variable Disease Courses in Siblings with Stargardt Disease. | Valkenburg D | Ophthalmology | 2019 | PMID: 31522899 |
| Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy. | Jespersgaard C | Scientific reports | 2019 | PMID: 30718709 |
| Mutation Spectrum of the ABCA4 Gene in a Greek Cohort with Stargardt Disease: Identification of Novel Mutations and Evidence of Three Prevalent Mutated Alleles. | Smaragda K | Journal of ophthalmology | 2018 | PMID: 29854428 |
| Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. | Birtel J | Scientific reports | 2018 | PMID: 29555955 |
| ABCA4 midigenes reveal the full splice spectrum of all reported noncanonical splice site variants in Stargardt disease. | Sangermano R | Genome research | 2018 | PMID: 29162642 |
| Mutation Spectrum of the ABCA4 Gene in 335 Stargardt Disease Patients From a Multicenter German Cohort-Impact of Selected Deep Intronic Variants and Common SNPs. | Schulz HL | Investigative ophthalmology & visual science | 2017 | PMID: 28118664 |
| Whole Genome Sequencing Increases Molecular Diagnostic Yield Compared with Current Diagnostic Testing for Inherited Retinal Disease. | Ellingford JM | Ophthalmology | 2016 | PMID: 26872967 |
| Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies. | Eisenberger T | PloS one | 2013 | PMID: 24265693 |
| ABCA4 disease progression and a proposed strategy for gene therapy. | Cideciyan AV | Human molecular genetics | 2009 | PMID: 19074458 |
| Peripapillary atrophy in Stargardt disease. | Hwang JC | Retina (Philadelphia, Pa.) | 2009 | PMID: 18854780 |
| ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies. | Kitiratschky VB | European journal of human genetics : EJHG | 2008 | PMID: 18285826 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Correlation of clinical and genetic findings in Hungarian patients with Stargardt disease. | Hargitai J | Investigative ophthalmology & visual science | 2005 | PMID: 16303926 |
| ABCA4 gene sequence variations in patients with autosomal recessive cone-rod dystrophy. | Fishman GA | Archives of ophthalmology (Chicago, Ill. : 1960) | 2003 | PMID: 12796258 |
| Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotype-phenotype correlation. | Gerth C | Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie | 2002 | PMID: 12192456 |
| Mutational scanning of the ABCR gene with double-gradient denaturing-gradient gel electrophoresis (DG-DGGE) in Italian Stargardt disease patients. | Fumagalli A | Human genetics | 2001 | PMID: 11702214 |
| A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration. | Rivera A | American journal of human genetics | 2000 | PMID: 10958763 |
| Phenotypic variations in a family with retinal dystrophy as result of different mutations in the ABCR gene. | Klevering BJ | The British journal of ophthalmology | 1999 | PMID: 10413692 |
| Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. | Lewis RA | American journal of human genetics | 1999 | PMID: 9973280 |
| Organization of the ABCR gene: analysis of promoter and splice junction sequences. | Allikmets R | Gene | 1998 | PMID: 9666097 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR. | Cremers FP | Human molecular genetics | 1998 | PMID: 9466990 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA4 | - | - | - | - |
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Text-mined citations for rs61751407 ...
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 Dec 15, 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.