Submissions for variant NM_000350.3(ABCA4):c.4070C>T (p.Ala1357Val)

dbSNP: rs552517556

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001244465	SCV001417687	pathogenic	not provided	2023-03-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ala1357 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22229821, 23755871, 29847635). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 969178). This missense change has been observed in individual(s) with Stargardt disease (PMID: 26311262, 32619608; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1357 of the ABCA4 protein (p.Ala1357Val).
GeneDx	RCV001244465	SCV001795859	likely pathogenic	not provided	2019-10-08	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26311262, 32619608)
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004814000	SCV005071112	likely pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782683	SCV005394727	pathogenic	Retinitis pigmentosa	2024-09-24	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.4070C>T (p.Ala1357Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250020 control chromosomes. c.4070C>T has been reported in the literature in multiple individuals affected with Retinitis Pigmentosa and STGD1 (example, Khan_2020, Tracewska_2019, Zhu_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32307445, 34321860, 33732702). ClinVar contains an entry for this variant (Variation ID: 969178). Based on the evidence outlined above, the variant was classified as pathogenic.