ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.466A>G (p.Ile156Val) (rs62646863)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000085663 SCV000321327 uncertain significance not provided 2018-11-09 criteria provided, single submitter clinical testing The I156V variant has been reported in a patient diagnosed with Stargardt disease and was absent from 96 control alleles (Papaioannou et al., 2000). The I156V variant has also been reported as a polymorphism (Riveiro-Alvarez et al.,2009). The NHLBI Exome Sequencing Project and the 1000 Genomes Project reports that I156V was observed in 13/8600 alleles from individuals of European background, in 1/28 alleles from individuals of Spanish background and in 2/196 alleles from individuals of Italian background indicating it may be a rare benign variant in the European population. The I156V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (R152Q, I153L, E161K, G172S) have been reported in the Human Gene Mutation Database in association with ABCA4-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000085663 SCV000700683 uncertain significance not provided 2016-10-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622993 SCV000741006 uncertain significance Inborn genetic diseases 2015-08-07 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626667 SCV000747369 uncertain significance Abnormal retinal morphology 2017-01-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764207 SCV000895210 uncertain significance Cone-rod dystrophy 3; Age-related macular degeneration 2; Stargardt disease 1; Retinitis pigmentosa 19 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000085663 SCV001110381 likely benign not provided 2020-11-18 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085663 SCV001147341 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001878 SCV001159602 uncertain significance not specified 2019-02-15 criteria provided, single submitter clinical testing The ABCA4 c.466A>G; p.Ile156Val variant (rs62646863) is reported in the literature in individuals affected with retinis pigmentosa, Stargardt disease, or another retinopathy, though it has not been demonstrated to be disease-causing (Ducroq 2002, Oldani 2012, Papaioannou 2000, Passerini 2010, Riveiro-Alvarez 2009, Valverde 2007). While this variant has been described in an affected individual with a second pathogenic variant (Ducroq 2002), it has also been described in healthy controls (Riveiro-Alvarez 2009) and in affected individuals carrying two other pathogenic variants that could explain their symptoms (Oldani 2012, Passerini 2010). The p.Ile156Val variant is found in the Latino population with an overall allele frequency of 0.33% (117/35438 alleles, including one homozygote) in the Genome Aggregation Database. The isoleucine at codon 156 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to conflicting information, the clinical significance of the p.Ile156Val variant is uncertain at this time. References: Ducroq D et al. The ABCA4 gene in autosomal recessive cone-rod dystrophies. Am J Hum Genet. 2002 Dec;71(6):1480-2. Oldani M et al. Clinical and molecular genetic study of 12 Italian families with autosomal recessive Stargardt disease. Genet Mol Res. 2012 Dec 17;11(4):4342-50. Papaioannou M et al. An analysis of ABCR mutations in British patients with recessive retinal dystrophies. Invest Ophthalmol Vis Sci. 2000 Jan;41(1):16-9. Passerini I et al. Novel mutations in of the ABCR gene in Italian patients with Stargardt disease. Eye (Lond). 2010 Jan;24(1):158-64. Riveiro-Alvarez R et al. Frequency of ABCA4 mutations in 278 Spanish controls: an insight into the prevalence of autosomal recessive Stargardt disease. Br J Ophthalmol. 2009 Oct;93(10):1359-64. Valverde D et al. Spectrum of the ABCA4 gene mutations implicated in severe retinopathies in Spanish patients. Invest Ophthalmol Vis Sci. 2007 Mar;48(3):985-90.
Illumina Clinical Services Laboratory,Illumina RCV001100155 SCV001256661 likely benign ABCA4-Related Disorders 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Retina International RCV000085663 SCV000117803 not provided not provided no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504910 SCV000598982 likely benign Stargardt disease 1 2015-01-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000085663 SCV001549001 uncertain significance not provided no assertion criteria provided clinical testing The ABCA4 p.Ile156Val variant was identified in 22 of 9152 proband chromosomes (freq=0.0024) from individuals or families with ABCA4-associated diseases, including Stargardt disease, retinitis pigmentosa and retinal dystrophies; the variant was also found in 5 of 348 chromosomes (freq=0.014) from healthy controls (Fujinami_2013_PMID:23982839; Cornelis_2017_PMID:28044389; Oldani_2012_PMID:23096905; Zernant_2011_PMID:21911583; Riviero-Alvarez_2009_PMID:18977788; Ducrog_2002_PMID:12515255; Papaioannou_2000_PMID:10634594, Valverde_2007_PMID:17325136; Passerini_2010_PMID:19265867). The variant was also identified in dbSNP (ID: rs62646863), Cosmic, LOVD 3.0 and ClinVar (classified as a VUS by GeneDx in 2017, EGL Genetic Diagnostics in 2016, Ambry Genetics in 2015, Center for Mendelian Genomics at University Medical Centre Ljubjana in 2017 and classified as likely benign by NIHR Bioresource Rare Diseases, University of Cambridge in 2015). The p.Ile156Val variant was identified in control databases in 408 of 282784 chromosomes (1 homozygous) at a frequency of 0.001443 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: Latino in 117 of 35438 chromosomes (freq: 0.003302), Other in 18 of 7226 chromosomes (freq: 0.002491), Ashkenazi Jewish in 21 of 10368 chromosomes (freq: 0.002025), European (non-Finnish) in 242 of 129102 chromosomes (freq: 0.001874), African in 4 of 24960 chromosomes (freq: 0.00016), European (Finnish) in 3 of 25122 chromosomes (freq: 0.000119), South Asian in 2 of 30614 chromosomes (freq: 0.000065), and East Asian in 1 of 19954 chromosomes (freq: 0.00005). The I156V variant was identified in 2/29 families with ABCA4-related conditions, one with Stargardt disease and one with cone dystrophy, although the variant was not suggested to be causal in either case (Gonz√°lez-del Pozo_2018_PMID:30190494). The variant was also identified in a proband with early-onset (diagnosed at 14) retinitis pigmentosa, however this variant was suggested to be benign (Hubshman_2018_PMID:29272404). The p.Ile156 residue is not conserved in mammals and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein. In addition, 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.
Clinical Genetics,Academic Medical Center RCV000085663 SCV001924739 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000085663 SCV001957626 likely benign not provided no assertion criteria provided clinical testing

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