NM_000350.3(ABCA4):c.6729+5_6729+19del AND not provided

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 13, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000497773.34

Allele description [Variation Report for NM_000350.3(ABCA4):c.6729+5_6729+19del]

NM_000350.3(ABCA4):c.6729+5_6729+19del

Gene:

ABCA4:ATP binding cassette subfamily A member 4 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

1p22.1

Genomic location:

Preferred name:

NM_000350.3(ABCA4):c.6729+5_6729+19del

HGVS:

NC_000001.11:g.93997843_93997857del
NG_009073.1:g.128294_128308del
NG_009073.2:g.128292_128306del
NM_000350.3:c.6729+5_6729+19delMANE SELECT
NC_000001.10:g.94463398_94463412del
NC_000001.10:g.94463399_94463413del
NM_000350.2:c.6729+5_6729+19del
NM_000350.2:c.6729+5_6729+19delGTTGGCCCTGGGGCA

Links:

dbSNP: rs749526785

NCBI 1000 Genomes Browser:

rs749526785

Molecular consequence:

NM_000350.3:c.6729+5_6729+19del - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000589300	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Sep 20, 2016)	germline	clinical testing	Citation Link,
SCV000700938	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (May 23, 2017)	germline	clinical testing	Citation Link,
SCV001392513	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 13, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 20554613, 25283059, 27583828, 28041643, 29925512, 17576681, 9536098, 29162642, 28492532
SCV001447679	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001501905	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Oct 1, 2020)	germline	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	5	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Homozygosity mapping in patients with cone-rod dystrophy: novel mutations and clinical characterizations.

Littink KW, Koenekoop RK, van den Born LI, Collin RW, Moruz L, Veltman JA, Roosing S, Zonneveld MN, Omar A, Darvish M, Lopez I, Kroes HY, van Genderen MM, Hoyng CB, Rohrschneider K, van Schooneveld MJ, Cremers FP, den Hollander AI.

Invest Ophthalmol Vis Sci. 2010 Nov;51(11):5943-51. doi: 10.1167/iovs.10-5797. Epub 2010 Jun 16.

PubMed [citation]

PMID:: 20554613
PMCID:: PMC3061516

Quantitative fundus autofluorescence distinguishes ABCA4-associated and non-ABCA4-associated bull's-eye maculopathy.

Duncker T, Tsang SH, Lee W, Zernant J, Allikmets R, Delori FC, Sparrow JR.

Ophthalmology. 2015 Feb;122(2):345-55. doi: 10.1016/j.ophtha.2014.08.017. Epub 2014 Oct 3.

PubMed [citation]

PMID:: 25283059
PMCID:: PMC4306619

See all PubMed Citations (10)

Details of each submission

From GeneDx, SCV000589300.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The c.6729+5_6729+19del15 variant has been reported in association with ABCA4-related eye disorders (Littink et al., 2010; Fujinami et al. 2013; Duncker et al., 2015). Upon examining the phenotypes and ages-of-onset associated with different variants, it was observed that the c.6729+5_6729+19del15 variant is associated with a very early age-of-onset with the median age-of-onset being 5 years (Fakin et al., 2016). The c.6729+5_6729+19del15 variant was not observed in approximately 6,500 individuals of European and African American ancestry in an external variant database, indicating it is not a common benign variant in these populations. Several in-silico splice prediction models predict that c.6729+5_6729+19del15 either damages or destroys the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is a likely pathogenic variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000700938.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From Invitae, SCV001392513.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change falls in intron 48 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 (rs749526785, gnomAD 0.06%). This variant has been observed in individuals with bullseye maculopathy, autosomal recessive retinitis pigmentosa, retinal degeneration, cone-rod dystrophy, and Stargardt disease (PMID: 20554613, 25283059, 27583828, 28041643, 29925512). This variant is also known as c.6729+4del1. ClinVar contains an entry for this variant (Variation ID: 283573). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 29162642). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447679.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV001501905.21

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		5	not provided	not provided	not provided

Last Updated: Sep 8, 2024

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