Submissions for variant NM_000350.3(ABCA4):c.3259G>A (p.Glu1087Lys)

gnomAD frequency: 0.00001  dbSNP: rs61751398

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085562	SCV001228211	pathogenic	not provided	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1087 of the ABCA4 protein (p.Glu1087Lys). This variant is present in population databases (rs61751398, gnomAD 0.01%). This missense change has been observed in individual(s) with Stargardt disease, Leber congenital amaurosis, or cone-rod dystrophy (PMID: 9054934, 19265867, 22264887, 28559085, 30576320). 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: 99211). 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 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCA4 function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075833	SCV001241472	pathogenic	Retinal dystrophy	2019-07-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085562	SCV001249468	pathogenic	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199228	SCV001370265	pathogenic	Age related macular degeneration 2	2019-03-17	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP2,PP3. This variant was detected in homozygous state.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814057	SCV001755586	pathogenic	Abnormality of the eye	2021-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000085562	SCV001804262	pathogenic	not provided	2021-11-12	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect with reduced protein expression and decreased ATPase activity (Sun et al., 2000); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12824224, 22264887, 20128570, 11328725, 11702214, 11017087, 23883535, 9054934, 14709597, 27820952, 32845050, 29925512, 30204727, 32619608, 28559085, 30576320, 19265867)
3billion, Medical Genetics	RCV001808323	SCV002058562	pathogenic	Retinitis pigmentosa 19	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099211, PMID:9054934, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099212,VCV001068257, PMID:14517951,29925512, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.966, 3CNET: 0.994, PP3_P). A missense variant is a common mechanism associated with Retinitis pigmentosa 19 (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetics and Molecular Pathology, SA Pathology	RCV002466427	SCV002761865	pathogenic	Cone-rod dystrophy 3	2021-01-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002498455	SCV002813171	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-02-28	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075833	SCV005070889	pathogenic	Retinal dystrophy	2017-01-01	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001075833	SCV005420757	pathogenic	Retinal dystrophy	2024-10-04	criteria provided, single submitter	research	PS3,PM3,PM2,PP3,PM5
Retina International	RCV000085562	SCV000117699	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV004732669	SCV005363178	pathogenic	ABCA4-related disorder	2024-08-30	no assertion criteria provided	clinical testing	The ABCA4 c.3259G>A variant is predicted to result in the amino acid substitution p.Glu1087Lys. This variant is reported in the compound heterozygous state in many individuals with Stargardt disease or ABCA4-related retinal disease (Allikmets et al. 1997. PubMed ID: 9054934; Stone et al. 2017. PubMed ID: 28559085; Karali et al. 2022. PubMed ID: 36460718; Bianco et al. 2023. PubMed ID: 37498587). The p.Glu1087Lys amino acid change is located within the well-defined Walker A motif of nucleotide-binding-domain 1 that is critical for binding and ATP hydrolysis (Curtis et al. 2020. PubMed ID: 32845050). Site-directed mutagenesis revealed that this variant exhibited diminished protein expression compared to the wildtype ABCA4 protein (Curtis et al. 2020. PubMed ID: 32845050). Individuals with this variant are reported to have severe phenotypes with an age of onset before 10 years (Fakin et al. 2016. PubMed ID: 27820952). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD and has been reported as pathogenic by many submitters to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/99211/). Taken together, this variant is interpreted as pathogenic.