ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.6079C>T (p.Leu2027Phe) (rs61751408)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000008332 SCV000281947 pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085785 SCV000329049 pathogenic not provided 2018-07-16 criteria provided, single submitter clinical testing The L2027F variant has been reported previously is association with ABCA4-related disorders (Webster et al, 2001; Briggs et al, 2001; Allikmets et al., 1997). The L2027F variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L2027F 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 conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In vitro functional studies demonstrated that the presence of L2027F significantly altered the ATPase function of the protein by both increasing the binding affinity and decreasing the rate of hydrolysis (Biswas et al., 2000). We interpret L2027F as a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000085785 SCV000700895 pathogenic not provided 2018-06-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763438 SCV000894205 pathogenic Cone-rod dystrophy 3; Age-related macular degeneration 2; Stargardt disease 1; Retinitis pigmentosa 19 2018-10-31 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000826132 SCV000967648 pathogenic Stargardt disease 2016-11-10 criteria provided, single submitter clinical testing The p.Leu2027Phe variant in ABCA4 has been reported in over 30 individuals with Stargardt disease, including 28 compound heterozygous and 3 homozygous individua ls (Allikmets 1997, Bertelsen 2014, Heathfield 2013, Fujinami 2013). Of note, t he individuals homozygous for this variant presented with a later onset and mild er phenotype (Fujinami 2013, Heathfield 2013). The variant has been identified i n 23/66736 of European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://; dbSNP rs61751408). Although this variant has been seen in the general population, its frequency is low enough to be consistent wit h a recessive carrier frequency. In vitro functional studies provide some evide nce that the p.Leu2027Phe variant may impact protein function (Biswas 2000). In summary, this variant meets criteria to be classified as pathogenic for Stargard t disease in an autosomal recessive manner based upon observation in patients wi th this disease and functional evidence.
Invitae RCV000085785 SCV001235490 pathogenic not provided 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 2027 of the ABCA4 protein (p.Leu2027Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs61751408, ExAC 0.03%). This variant has been observed to segregate with Stargardt disease in families (PMID: 28559085). ClinVar contains an entry for this variant (Variation ID: 7882). This variant has been reported to affect ABCA4 protein function (PMID: 29847635). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074885 SCV001240489 pathogenic Retinal dystrophy 2019-08-12 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085785 SCV001247598 pathogenic not provided 2016-11-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000008333 SCV001440311 pathogenic Cone-rod dystrophy 3 2019-01-01 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000085785 SCV001448776 pathogenic not provided 2018-05-11 criteria provided, single submitter clinical testing
Institute of Medical Molecular Genetics, University of Zurich RCV000008332 SCV001548038 likely pathogenic Stargardt disease 1 2021-01-30 criteria provided, single submitter clinical testing
OMIM RCV000008332 SCV000028540 pathogenic Stargardt disease 1 2003-06-01 no assertion criteria provided literature only
OMIM RCV000008333 SCV000028541 pathogenic Cone-rod dystrophy 3 2003-06-01 no assertion criteria provided literature only
Retina International RCV000085785 SCV000117927 not provided not provided no assertion provided not provided
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000085785 SCV001551440 pathogenic not provided no assertion criteria provided clinical testing The ABCA4 p.Leu2027Phe variant was identified in 44 of 428 proband chromosomes (frequency: 0.103) from individuals or families with Stargardt Disease, Cone-Rod dystrophy or ABCA4-Associated Retinopathies (Maugeri_1999_PMID:10090887; Bertelsen_2014_PMID:24713488; Heathfield_2013_PMID:23695285, Fishman_2003_PMID:12796258). The variant was identified in dbSNP (ID: rs61751408) and in ClinVar (classified as pathogenic by EGL Genetic Diagnostics, Fulgent Genetics, GeneDx and Institute of Human Genetics, Univ. Regensburg). The variant was also identified in control databases in 56 of 282804 chromosomes at a frequency of 0.000198 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 45 of 129122 chromosomes (freq: 0.000349), African in 8 of 24968 chromosomes (freq: 0.00032), Other in 1 of 7222 chromosomes (freq: 0.000139) and Latino in 2 of 35436 chromosomes (freq: 0.000056); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) and South Asian populations. 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. The p.Leu2027 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. However, in vitro functional studies of the L2027F variant have demonstrated biochemical defects leading to lower protein functionality and altered ATPase function (Sun_2000_PMID: 11017087; Biswas_2000_PMID: 11123914). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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