Submissions for variant NM_000350.3(ABCA4):c.5642C>T (p.Ala1881Val)

gnomAD frequency: 0.00004  dbSNP: rs369973540

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001058803	SCV001223399	pathogenic	not provided	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1881 of the ABCA4 protein (p.Ala1881Val). This variant is present in population databases (rs369973540, gnomAD 0.02%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 22661472, 30060493; internal data). 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: 853893). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 80%. This variant disrupts the p.Ala1881 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 26355662), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001058803	SCV001446894	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471022	SCV002767739	likely pathogenic	Cone-rod dystrophy 3	2020-10-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease (MIM#248200). (I) 0106 - This gene is associated with autosomal recessive disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (21 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC-2 family transporter protein domain (Decipher). (I) 0704 - Another missense variant (p.(Ala1881Gly)) comparable to the one identified in this case has limited previous evidence for pathogenicity, and has previously been reported in a patient with retinitis pigmentosa and cone-rod dystrophy (PMID: 26355662). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals with Stargardt disease (Clinvar, PMID: 22661472, PMID: 30060493). (SP) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004813655	SCV005072477	likely pathogenic	Retinal dystrophy	2018-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005029638	SCV005661317	likely pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-04-23	criteria provided, single submitter	clinical testing