Submissions for variant NM_000350.3(ABCA4):c.4793C>A (p.Ala1598Asp)

gnomAD frequency: 0.00003  dbSNP: rs61750155

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408465	SCV000281906	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085674	SCV000511901	pathogenic	not provided	2022-03-10	criteria provided, single submitter	clinical testing	Published functional studies demonstrate A1598D results in reduced basal activity, supporting a damaging effect (Curtis et al., 2020); This variant is associated with the following publications: (PMID: 27014590, 23105016, 20696155, 10958761, 22025579, 28118664, 29178665, 28365912, 19074458, 25525159, 26103963, 29925512, 28559085, 32845050, 31589614, 32619608, 34426522, 32783370)
Invitae	RCV000085674	SCV001213077	pathogenic	not provided	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1598 of the ABCA4 protein (p.Ala1598Asp). This variant is present in population databases (rs61750155, gnomAD 0.009%). This missense change has been observed in individual(s) with retinal disease (PMID: 10958761, 19074458, 23105016, 28559085). 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: 99321). 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 with a positive predictive value of 95%. This variant disrupts the p.Ala1598 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been observed in individuals with ABCA4-related conditions (PMID: 26161775), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074177	SCV001239747	pathogenic	Retinal dystrophy	2019-02-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000085674	SCV002019755	pathogenic	not provided	2021-11-08	criteria provided, single submitter	clinical testing
3billion	RCV001808326	SCV002058292	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: VCV000099321, PMID:10958761, PS1_S). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PM3_S). A different missense change at the same codon has been reported to be associated with ABCA4 related disorder (PMID:26161775, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.685, 3CNET: 0.955, 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: 0.000024, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen	RCV000085674	SCV002544292	likely pathogenic	not provided	2022-05-01	criteria provided, single submitter	clinical testing	ABCA4: PM3:Strong, PM2, PS3:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387758	SCV004100307	pathogenic	Retinitis pigmentosa	2023-09-05	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.4793C>A (p.Ala1598Asp) results in a non-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. The variant allele was found at a frequency of 2.4e-05 in 250090 control chromosomes (gnomAD). c.4793C>A has been reported in the literature in multiple individuals affected with autosomal recessive Stargardt disease (examples: Passerini_2010 and Mejecase_2020). 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: 32783370, 19265867). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Retina International	RCV000085674	SCV000117814	not provided	not provided		no assertion provided	not provided
NEI Ophthalmic Genomics Laboratory, National Institutes of Health	RCV000085674	SCV000119179	not provided	not provided		no assertion provided	not provided
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002825	SCV001160842	pathogenic	Stargardt disease	2019-06-23	no assertion criteria provided	research
Faculty of Health Sciences, Beirut Arab University	RCV001257846	SCV001434613	pathogenic	Autosomal recessive retinitis pigmentosa	2012-10-26	no assertion criteria provided	literature only
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000085674	SCV002037365	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000085674	SCV002037810	likely pathogenic	not provided		no assertion criteria provided	clinical testing