Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001321279 | SCV001512101 | likely pathogenic | not provided | 2022-08-16 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 812194). This missense change has been observed in individual(s) with clinical features of ABCA4-related conditions and/or Stargardt disease (PMID: 31456290; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 2129 of the ABCA4 protein (p.Ser2129Asn). This variant also falls at the last nucleotide of exon 46, which is part of the consensus splice site for this exon. |
| Mendelics | RCV002249614 | SCV002516198 | likely pathogenic | Age related macular degeneration 2 | 2022-05-04 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323781 | SCV004028623 | uncertain significance | not specified | 2023-07-03 | criteria provided, single submitter | clinical testing | Variant summary: ABCA4 c.6386G>A (p.Ser2129Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Computational tool(s) predict a significant impact on normal splicing: One predict the variant weakens the canonical 5' splicing donor site. Three other tools have not predicted this natural splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was not found in 251434 control chromosomes in gnomAD, and was reported at a frequency of 0.0008 in 11412 control chromosomes in an Ashkenazi Jewish cohort (Hanany_2018). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6386G>A has been reported in the literature as a presumed compound heterozygous genotype in at-least one individual from a single family affected with features of Inherited Retinal Disease (specifically conerod dystrophy, CRD) (example, Sharon_2019). This report does not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two splicing Variants that disrupt the consensus splice site are associated with disease (c.6386+1G>A, c.6386+2C>G, PATH in ClinVar). The following publications have been ascertained in the context of this evaluation (PMID: 31456290, 29706639). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (pathogenic =1, likely pathogenic = 2). Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Sharon lab, |
RCV002267744 | SCV001160819 | pathogenic | Cone-rod dystrophy | 2019-06-23 | no assertion criteria provided | research |