ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.5908C>T (p.Leu1970Phe)

gnomAD frequency: 0.00362  dbSNP: rs28938473
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000259062 SCV000202086 likely benign not specified 2018-06-22 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408598 SCV000281940 likely pathogenic Severe early-childhood-onset retinal dystrophy 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085773 SCV000490380 likely benign not provided 2020-07-07 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 9781034, 25087612, 9295268, 23953153, 9973280, 10958763, 12515255, 22264887, 28118664, 27408750, 28157192, 29925512, 30718709, 33633436)
CeGaT Center for Human Genetics Tuebingen RCV000085773 SCV000574763 uncertain significance not provided 2019-08-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000778995 SCV000915436 uncertain significance ABCA4-Related Disorders 2017-09-01 criteria provided, single submitter clinical testing The ABCA4 c.5908C>T (p.Leu1970Phe) missense variant has been reported in at least eleven studies in which it is found in at least thirteen individuals with ABCA4-related disorders including in three in a compound heterozygous state and in ten in a heterozygous state (Allikmets et al. 1997; Rozet et al 1998; Lewis et al 1999; Rivera et al 2000; Souied et al 2000; Webster et al 2001; Bernstein et al 2002; Ducroq et al. 2002; Riveiro-Alvarez et al 2009; Thiadens et al. 2012; Schulz et al. 2017). The individuals exhibited a variety of phenotypes. Two of the compound heterozygous individuals were diagnosed with Stargardt disease and one with a related eye disorder, late-onset fundus flavimaculatus. Of the ten heterozygous individuals, six, including one set of three siblings and one pair of siblings, were diagnosed with dominantly inherited age-related macular degeneration. A second variant was not detected in the remaining four heterozygous individuals, two of whom were diagnosed with recessively inherited Stargardt disease, and two with recessively inherited cone or cone-rod dystrophy. The p.Leu1970Phe variant was reported in two of 1608 control chromosomes (Allikmets et al. 1997; Rozet et al 1998; Rivera et al 2000; Riveiro-Alvarez et al 2009) and is reported at a frequency of 0.00596 in the European population of the 1000 Genomes Project. The p.Leu1970Phe variant has also been reported in a homozygous state in three individuals from the Genome Aggregation Database, which may be inconsistent with the clinical significance of this variant. In vitro expression analysis in HEK293T cells found that the p.Leu1970Phe variant is associated with reduced protein expression and ATP-binding, which is suggestive of protein misfolding (Shroyer et al. 2001). The p.Leu1970Phe variant occurs at an amino acid position that is conserved in both the ATP-binding cassette superfamily and ABCA4 mouse ortholog (Rozet et al. 1998). Based on the evidence, the p.Leu1970Phe variant is classified as a variant of unknown significance but suspicious for pathogenicity for ABCA4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000085773 SCV001121839 benign not provided 2021-12-16 criteria provided, single submitter clinical testing
Blueprint Genetics RCV001073250 SCV001238786 uncertain significance Retinal dystrophy 2018-08-30 criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV000408598 SCV002028300 uncertain significance Severe early-childhood-onset retinal dystrophy 2021-08-27 criteria provided, single submitter clinical testing
OMIM RCV000008346 SCV000028554 pathogenic Stargardt disease 1998-05-01 no assertion criteria provided literature only
Retina International RCV000085773 SCV000117915 not provided not provided no assertion provided not provided
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787515 SCV000926483 pathogenic Vitreoretinopathy 2018-04-01 no assertion criteria provided research

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