ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1928T>G (p.Val643Gly) (rs61754024)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408583 SCV000281837 likely pathogenic Stargardt disease 1 2016-01-01 criteria provided, single submitter clinical testing
GeneDx RCV000085446 SCV000321342 uncertain significance not provided 2017-10-09 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ABCA4 gene. The V643G variant has been published previously in association with ABCA4-related disorders; however, the variant was only reported in the heterozygous state and was not observed with other pathogenic ABCA4 variants (Allikmets et al., 1997; Ścieżyńska et al., 2015; Rosenberg et al., 2007). The NHLBI Exome Sequencing Project reports V643G was observed in 24/8600 (0.28%) alleles from individuals of Europeean background, and the 1000 Genomes Project Consortium reports the variant was observed in 5/1006 (0.50%) alleles from individuals of European background, indicating it may be a rare variant in this population. The variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000085446 SCV000608481 uncertain significance not provided 2018-12-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000085446 SCV000700703 uncertain significance not provided 2016-12-01 criteria provided, single submitter clinical testing
Invitae RCV000085446 SCV001035550 likely benign not provided 2019-12-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000616 SCV001157612 uncertain significance not specified 2019-02-15 criteria provided, single submitter clinical testing The ABCA4 c.1928T>G; p.Val643Gly variant (rs61754024) is reported in the medical literature in individuals with retinopathy in the heterozygous state without an additional pathogenic ABCA4 variant (Birtel 2018, Rosenberg 2007, Scienzynska 2016) and was originally described at a similar frequency in affected and unaffected individuals (Allikmets 1997). The variant is reported in the ClinVar database (Variation ID: 99102) and in the European (non-Finnish) population with an overall allele frequency of 0.3% (389/128892 alleles including 1 homozygote) in the Genome Aggregation Database. The valine at this position is highly conserve but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of the variant is uncertain at this time. References: Allikmets R et al. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. 1997 Sep 19;277(5333):1805-7. Birtel J et al. Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy. Sci Rep. 2018 Mar 19;8(1):4824 Rosenberg T et al. N965S is a common ABCA4 variant in Stargardt-related retinopathies in the Danish population. Mol Vis. 2007 Oct 17;13:1962-9. 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.
Blueprint Genetics RCV001074170 SCV001239740 uncertain significance Retinal dystrophy 2019-02-19 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001098278 SCV001254632 uncertain significance 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Retina International RCV000085446 SCV000117583 not provided not provided no assertion provided not provided

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