ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.6148G>C (p.Val2050Leu) (rs41292677)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000259072 SCV000110530 benign not specified 2016-11-17 criteria provided, single submitter clinical testing
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000008335 SCV000281950 likely pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000393715 SCV000359223 likely benign Retinitis Pigmentosa, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000285333 SCV000359224 likely benign Cone-Rod Dystrophy, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000340261 SCV000359225 likely benign Stargardt Disease, Recessive 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000393726 SCV000359226 likely benign Macular degeneration 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000078671 SCV000511911 uncertain significance not provided 2018-11-07 criteria provided, single submitter clinical testing The V2050L variant in the ABCA4 gene has been reported previously in association with Stargardt disease, macular dystrophy, cone-rod dystrophy, and age-related macular degeneration (Lewis et al., 1999; Wiszniewski et al., 2005; Poloschek et al., 2010; Fritsche et al., 2012; Corton et al., 2013). Poloschek et al. (2010) reported that V2050L heterozygous carriers show centrally reduced mfERG amplitudes and additional minor fundus abnormalities, which suggested that the V2050L variant in the heterozygous state is capable of mildly reducing macular function without an additional pathogenic variant on the second allele. However, the V2050L variant is observed in 202/34420 (0.5869%) alleles from individuals of Latino background and 787/277174 (0.2839%) global alleles, with one homozygote reported (Lek et al., 2016). The V2050L variant is a conservative amino acid substitution, which occurs at a position that is conserved across species. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret V2050L as a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000778139 SCV000914269 uncertain significance ABCA4-Related Disorders 2019-04-05 criteria provided, single submitter clinical testing Across a selection of available literature, the ABCA4 c.6148G>C (p.Val2050Leu) missense variant has been reported in at least seven individuals affected with Stargardt macular degeneration including in three in a compound heterozygous state, in one in a heterozygous state and in at least three with unknown zygosity. The variant has also been reported in two brothers affected with cone-rod dystrophy in a compound heterozygous state with a frameshift variant on the second allele, and in a heterozygous state in one individual affected with macular dystrophy (Allikmets et al. 1997; Lewis et al. 1999; Corton et al. 2013; Schulz et al. 2017; Haer-Wigman et al. 2017). The variant failed to segregate with the disorder in one family affected with autosomal recessive retinitis pigmentosa and in one with autosomal dominant macular dystrophy (Wiszniewski et al. 2005; Poloschek et al. 2010). The p.Val2050Leu variant has also been found as a complex allele in cis with either a stop-gained variant or a missense variant in individuals affected with ABCA4-related disorders (Sciezynska et al. 2016; Schulz et al. 2017). The variant was found in a heterozygous state in one of 1528 control individuals and in one unaffected parent (Allikmets et al. 1997; Lewis et al. 1999; Corton et al. 2013; Sciezynska et al. 2016). This variant is reported at a frequency of 0.028846 in Puerto Ricans from Puerto Rico from the 1000 Genomes Project and in one homozygote in the European (non-Finnish) population of the Genome Aggregation Database. Poloschek et al. (2010) showed that, upon ophthalmic examination, heterozygous carriers of the p.Val2050Leu variant display centrally reduced mfERG amplitudes and additional minor fundus abnormalities, suggesting that the p.Val2050Leu variant is capable of mildly reducing macular function in the heterozygous state without an additional pathogenic variant on the second allele. Based on the collective evidence the p.Val2050Leu 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 RCV000078671 SCV001037250 benign not provided 2020-12-05 criteria provided, single submitter clinical testing
Mendelics RCV000008335 SCV001135324 uncertain significance Stargardt disease 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078671 SCV001147323 uncertain significance not provided 2019-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283002 SCV001159506 uncertain significance none provided 2019-12-04 criteria provided, single submitter clinical testing The ABCA4 c.6148G>C; p.Val2050Leu variant (rs41292677) is reported in the literature in multiple individuals affected with Stargardt disease, retinitis pigmentosa, or a related retinal disorder (Allikmets 1997, Corton 2013, Haer-Wigman 2017, Sciezynska 2016, Wiszniewski 2005). This variant has been observed in trans to a pathogenic variant in affected individuals (Corton 2013); however, it has also been observed in cis to a nonsense variant in at least one study (Sciezynska 2016). The p.Val2050Leu variant is found in the Latino population with an overall allele frequency of 0.60% (211/35438 alleles) in the Genome Aggregation Database and is reported with conflicting classifications in ClinVar (Variation ID: 7884). The leucine at codon 2050 is highly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. Due to conflicting information, the clinical significance of the p.Val2050Leu variant is uncertain at this time. References: Allikmets R et al. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet. 1997 Mar;15(3):236-46. Corton M et al. Exome sequencing of index patients with retinal dystrophies as a tool for molecular diagnosis. PLoS One. 2013 Jun 14;8(6):e65574. Haer-Wigman L et al. Diagnostic exome sequencing in 266 Dutch patients with visual impairment. Eur J Hum Genet. 2017 May;25(5):591-599. Sciezynska A et al. Next-generation sequencing of ABCA4: High frequency of complex alleles and novel mutations in patients with retinal dystrophies from Central Europe. Exp Eye Res. 2016 Apr;145:93-99. Wiszniewski W et al. ABCA4 mutations causing mislocalization are found frequently in patients with severe retinal dystrophies. Hum Mol Genet. 2005 Oct 1;14(19):2769-78.
Blueprint Genetics RCV001075661 SCV001241289 uncertain significance Retinal dystrophy 2019-03-07 criteria provided, single submitter clinical testing
Institute of Medical Molecular Genetics, University of Zurich RCV000008335 SCV001548109 likely pathogenic Stargardt disease 1 2021-01-30 criteria provided, single submitter clinical testing
OMIM RCV000008335 SCV000028543 pathogenic Stargardt disease 1 2016-12-29 no assertion criteria provided literature only
Retina International RCV000078671 SCV000117933 not provided not provided no assertion provided not provided
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504806 SCV000599010 likely pathogenic Cone dystrophy 2015-01-01 no assertion criteria provided research
Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet RCV000787769 SCV000926774 pathogenic Retinitis pigmentosa 2018-04-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000078671 SCV001549292 uncertain significance not provided no assertion criteria provided clinical testing The ABCA4 p.Val2050Leu variant was identified in 13 of 2830 proband chromosomes (frequency: 0.00459) from individuals or families with inherited retinal diseases including macular dystrophy, cone-rod dystrophy and Stargardt disease (Haer-Wigman_2017_PMID:28224992; Carss_2017_PMID:28041643; Schulz_2017_PMID:28118664; Sciezynska_2016_PMID:26593885). A study of a family with macular dystrophy, cone dystrophy, and cone–rod dystrophy in five-generations identified variants in the PRPH2, ABCA4, and ROM1 genes; family members heterozygous for only the ABCA4 V2050L variant showed mildly reduced macular function with centrally reduced mfERG amplitudes and additional minor fundus abnormalities (Poloschek_2010_PMID:20335603). The V2050L variant was identified in dbSNP (ID: rs41292677), ClinVar (classified as benign 1x, likely benign 4x, VUS 2x, likely pathogenic 2x and pathogenic 1x) and LOVD 3.0 (classified as a VUS and likely pathogenic). The variant was also identified in control databases in 808 of 282834 chromosomes (1 homozygous) at a frequency of 0.002857 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 211 of 35438 chromosomes (freq: 0.005954), Ashkenazi Jewish in 50 of 10368 chromosomes (freq: 0.004823), Other in 29 of 7226 chromosomes (freq: 0.004013), European (non-Finnish) in 500 of 129166 chromosomes (freq: 0.003871), African in 13 of 24950 chromosomes (freq: 0.000521) and European (Finnish) in 5 of 25118 chromosomes (freq: 0.000199); it was not observed in the East Asian or South Asian populations. The p.Val2050 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The p.Val2050Leu variant occurs in the first base of the exon; this position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, only 2 of 4 in silico or computational prediction software programs (MaxEntScan, GeneSplicer) predict a greater than 10% 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.

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