NM_000350.3(ABCA4):c.4297G>A (p.Val1433Ile) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (11 submissions)
Last evaluated:: Jan 31, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000085627.53

Allele description [Variation Report for NM_000350.3(ABCA4):c.4297G>A (p.Val1433Ile)]

NM_000350.3(ABCA4):c.4297G>A (p.Val1433Ile)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

1p22.1

Genomic location:

Preferred name:

NM_000350.3(ABCA4):c.4297G>A (p.Val1433Ile)

HGVS:

NC_000001.11:g.94030483C>T
NG_009073.1:g.95667G>A
NG_009073.2:g.95665G>A
NM_000350.3:c.4297G>AMANE SELECT
NM_001425324.1:c.4075G>A
NP_000341.2:p.Val1433Ile
NP_001412253.1:p.Val1359Ile
NC_000001.10:g.94496039C>T
NM_000350.2:c.4297G>A
P78363:p.Val1433Ile

Protein change:

V1359I

Links:

UniProtKB: P78363#VAR_008449; dbSNP: rs56357060

NCBI 1000 Genomes Browser:

rs56357060

Molecular consequence:

NM_000350.3:c.4297G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001425324.1:c.4075G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000117766	Retina International	no classification provided	not provided	unknown	not provided
SCV000119178	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	no classification provided	not provided	not provided	not provided
SCV000228691	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Feb 15, 2015)	germline	clinical testing	Citation Link,
SCV001157693	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Sep 4, 2019)	germline	clinical testing	Citation Link,
SCV001248247	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Apr 1, 2023)	germline	clinical testing	Citation Link,
SCV001548668	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV001600164	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 31, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001922759	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001951445	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV002038195	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV002757194	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Nov 26, 2022)	germline	clinical testing	Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Retina International, SCV000117766.1

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

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

From NEI Ophthalmic Genomics Laboratory, National Institutes of Health, SCV000119178.1

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

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

From Eurofins Ntd Llc (ga), SCV000228691.5

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001157693.2

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

Description

The ABCA4 variant c.4297G>A; p.Val1433Ile (rs56357060) is reported in the medical literature in individuals with ABCA4-related disease as well as age related macular degeneration in the compound heterozygous state in a few individuals, but often without an additional pathogenic variant (Aguirre-Lamban 2009, Klevering 2004, Lewis 1999, Michaelides 2007, Song 2011, Souied 2000, Taylor 2017, Thiadens 2012, Webster 2001). The variant is reported in the ClinVar database (Variation ID: 99274) and in the Genome Aggregation Database in the general population with an allele frequency of 0.2% (470/282886 alleles including 1 homozygote). The amino acid at this position is highly conserved but computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. Considering available information, there is insufficient evidence to classify this variant with certainty. References: Aguirre-Lamban J et al. Molecular analysis of the ABCA4 gene for reliable detection of allelic variations in Spanish patients: identification of 21 novel variants. Br J Ophthalmol. 2009 May;93(5):614-21. Klevering BJ et al. Three families displaying the combination of Stargardt's disease with cone-rod dystrophy or retinitis pigmentosa. Ophthalmology. 2004 Mar;111(3):546-53. Lewis RA et al. Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease. Am J Hum Genet. 1999 Feb;64(2):422-34. Michaelides M et al. ABCA4 mutations and discordant ABCA4 alleles in patients and siblings with bull's-eye maculopathy. Br J Ophthalmol. 2007 Dec;91(12):1650-5. Song J et al. High-throughput retina-array for screening 93 genes involved in inherited retinal dystrophy. Invest Ophthalmol Vis Sci. 2011 Nov 25;52(12):9053-60. Souied EH et al. ABCR gene analysis in familial exudative age-related macular degeneration. Invest Ophthalmol Vis Sci. 2000 Jan;41(1):244-7. Taylor RL et al. Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease. Ophthalmology. 2017 Jul;124(7):985-991. Thiadens AA et al. Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. Ophthalmology. 2012 Apr;119(4):819-26 Webster AR et al. An analysis of allelic variation in the ABCA4 gene. Invest Ophthalmol Vis Sci. 2001 May;42(6):1179-89.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001248247.26

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

Description

ABCA4: PM1

#	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

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001548668.1

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

Description

The ABCA4 p.Val1433Ile variant was identified in 9 of 1492 proband chromosomes (frequency: 0.006) from individuals or families with stargardt disease, cone-rod dystrophy, age-related macular degeneration and retinitis pigmentosa (Schulz_2017_PMID:28118664; Thiadens_2012_PMID:22264887; Aguirre-Lamban_2009_PMID:19028736; Baum_2003_PMID:12592048; Lewis_1999_PMID:9973280). The variant was identified in dbSNP (ID: rs56357060), ClinVar (classified as likely pathogenic by Institute of Human Genetics, Univ. Regensburg and as a VUS by EGL Genetic Diagnostics and Illumina) and in LOVD 3.0 (classified as pathogenic once, a VUS four times and likely benign twice). The variant was also identified in control databases in 470 of 282886 chromosomes (1 homozygous) at a frequency of 0.001661 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 322 of 129192 chromosomes (freq: 0.002492), Other in 14 of 7226 chromosomes (freq: 0.001937), East Asian in 35 of 19952 chromosomes (freq: 0.001754), Latino in 56 of 35440 chromosomes (freq: 0.00158), European (Finnish) in 19 of 25118 chromosomes (freq: 0.000756), African in 16 of 24972 chromosomes (freq: 0.000641), South Asian in 7 of 30616 chromosomes (freq: 0.000229), and Ashkenazi Jewish in 1 of 10370 chromosomes (freq: 0.000096). The p.Val1433 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001600164.4

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001922759.1

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001951445.1

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

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV002038195.1

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

From GeneDx, SCV002757194.1

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

Description

Observed in patients with Stargardt disease in published literature who were reported to have V1433I on the same allele (in cis) with other ABCA4 variants or seen phase unknown with two other pathogenic ABCA4 variants, therefore questioning the pathogenicity of V1433I (Klevering et al., 2004; Lambertus et al., 2016; Murro et al., 2017; Birtel et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22995991, 34073554, 22025579, 27527345, 28002570, 28430335, 34426522, 20981092, 35119454, 29555955, 33090715, 15494742, 28341476, 32037395, 24409374, 22264887, 9973280)

#	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

Last Updated: Nov 10, 2024

Relating variation to medicine