ClinVar Miner

Submissions for variant NM_000350.3(ABCA4):c.1933G>A (p.Asp645Asn)

dbSNP: rs61749418
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000085447 SCV001215910 pathogenic not provided 2023-10-15 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 645 of the ABCA4 protein (p.Asp645Asn). This variant is present in population databases (rs61749418, gnomAD 0.004%). This missense change has been observed in individual(s) with Stargardt disease and retinitis pigmentosa (PMID: 9973280, 28559085, 29975949, 30029497, 31144483). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99103). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA4 protein function. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001074983 SCV001240592 pathogenic Retinal dystrophy 2017-11-12 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000085447 SCV001245786 pathogenic not provided 2017-06-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004689454 SCV005184466 pathogenic Retinitis pigmentosa 2024-05-28 criteria provided, single submitter clinical testing Variant summary: ABCA4 c.1933G>A (p.Asp645Asn) results in a conservative amino acid change located in the ABC-2 type transporter, transmembrane domain (IPR013525) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251094 control chromosomes. c.1933G>A has been reported in the literature in multiple compound heterozygous individuals affected with retinitis pigmentosa or Stargardt disease (e.g., Lewis_1999, Stone_2017, Wang_2018, Hu_2019). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 31543898, 9973280, 28559085, 30029497). ClinVar contains an entry for this variant (Variation ID: 99103). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV005025146 SCV005661407 pathogenic Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19 2024-05-31 criteria provided, single submitter clinical testing
Retina International RCV000085447 SCV000117584 not provided not provided no assertion provided not provided

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