Submissions for variant NM_000350.3(ABCA4):c.5603A>T (p.Asn1868Ile)

gnomAD frequency: 0.04126  dbSNP: rs1801466

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000085744	SCV000166748	benign	not provided	2019-01-28	criteria provided, single submitter	clinical testing	The variant in the ABCA4 gene that is indicated below was identified in this patient and is not currently known to cause an ABCA4-related disorder. The variant is observed in 8,580/129,074 (6.65%) alleles from individuals of non-Finnish European background and in 11,928/282,712 (4.22%) global alleles, including 364 homozygous individuals, in large population cohorts (Lek et al., 2016). However, some publications theorize N1868I may cause hypomorphic retinal dystrophy only when in trans with a pathogenic ABCA4 variant (Zernant et al., 2017; Runhart et al., 2018). Individuals who had the N1868I variant in trans with another ABCA4 pathogenic variant were reported to have late-onset Stargardt disease (Zernant et al., 2017; Runhart et al,. 2018).; This variant is associated with the following publications: (PMID: 26780318, 21330655, 32845050, 28118664, 11328725, 28446513, 27775217, 24265693, 11017087, 29555955, 29971439, 23443024, 30204727, 30480703, 30480704, 29925512, 30670881, 30643219, 31618761, 31456290, 32467599, 32037395)
Eurofins Ntd Llc (ga)	RCV000178424	SCV000230500	benign	not specified	2014-05-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV001097975	SCV000303765	established risk allele	ABCA4-related disorder	2024-03-05	criteria provided, single submitter	clinical testing	This variant is reported with a global allele frequency of 4.2% in gnomAD, with the highest population frequency being 6.6% in individuals of European (Non-Finnish) descent, including hundreds of homozygous individuals. Allele frequencies this high are most often associated with variants that are considered benign for Mendelian disease. However, statistical analyses have shown that this variant is significantly enriched in Stargardt patient populations compared to controls (Webster et al. 2001. PubMed ID: 11328725; Aguirre-Lamban et al. 2011. PubMed ID: 21330655). Large cohort studies of individuals with only one known pathogenic variant in ABCA4 found that this c.5603A>T (p.Asn1868Ile) variant could explain ~50% of those missing heritability cases (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Despite the enrichment in the patient population, the very high allele frequency has been used to estimate that the penetrance of this variant is less than 5% (Runhart et al. 2018. PubMed ID: 29971439). Additionally, it has been demonstrated that patients who harbor this variant have a more mild phenotype and an average age of onset in the 4th decade compared to the typical juvenile-onset associated with ABCA4 disease (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Functional studies have shown that this variant causes a small but significant decrease in the ATPase activity (Sun et al. 2000. PubMed ID: 11017087) and a decrease in substrate binding ability (Garces et al. 2021. PubMed ID: 33375396). This variant has often been found in cis with other ABCA4 variants such as c.2588G>C, c.5461-10T>C, and many others; forming a complex allele which can modify the penetrance and severity of disease (Zernant et al. 2017. PubMed ID: 28446513; Bauwens et al. 2019. PubMed ID: 30670881). Given all the evidence, we interpret c.5603A>T (p.Asn1868Ile) as a risk variant for mild and late-onset disease when in trans with a severe variant.
Illumina Laboratory Services, Illumina	RCV000293913	SCV000359264	likely benign	Cone-Rod Dystrophy, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000348932	SCV000359265	likely benign	Retinitis Pigmentosa, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000391356	SCV000359266	likely benign	Macular degeneration	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000309306	SCV000359267	likely benign	Stargardt Disease, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085744	SCV000493309	uncertain significance	not provided	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000721173	SCV001135331	uncertain significance	Severe early-childhood-onset retinal dystrophy	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001097975	SCV001254309	likely benign	ABCA4-related disorder	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197336	SCV001368030	uncertain significance	Age related macular degeneration 2	2019-06-27	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP2,PP3,BS1.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262623	SCV001440560	uncertain significance	Cone-rod dystrophy 3	2019-01-01	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous.
Institute of Medical Molecular Genetics, University of Zurich	RCV000721173	SCV001548165	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085744	SCV001731765	benign	not provided	2021-12-18	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001723669	SCV001950192	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Asn1868Ile variant in ABCA4 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM3, PM3, BP2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000721173	SCV002549835	established risk allele	Severe early-childhood-onset retinal dystrophy	2022-06-23	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_000350.3:c.67-2A>G
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815126	SCV005069856	uncertain significance	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000178424	SCV005725846	likely benign	not specified	2024-11-25	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.5603A>T (p.Asn1868Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.043 in 251362 control chromosomes in the gnomAD database, including 328 homozygotes. The observed variant frequency is approximately 30.45 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA4 causing Stargardt Disease phenotype (0.0014). c.5603A>T has been reported in the literature in individuals affected with Stargardt Disease and related disorders (e.g. Webster_2001, Zernant_2017). These reports do not provide unequivocal conclusions about association of the variant with Stargardt Disease. Co-occurrences with multiple other pathogenic variants have been reported in cis, providing supporting evidence for a benign role. Publications report experimental evidence evaluating an impact on protein function (e.g. Sun_2000, Garces_2020). These results showed little or no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 11328725, 33375396, 11017087, 28446513). ClinVar contains an entry for this variant (Variation ID: 99390). Based on the evidence outlined above, the variant was classified as likely benign.
Retina International	RCV000085744	SCV000117885	not provided	not provided		no assertion provided	not provided
Molecular Vision Laboratory	RCV000721173	SCV000852088	other	Severe early-childhood-onset retinal dystrophy	2018-09-10	no assertion criteria provided	clinical testing	Asn1868Ile has been found to be associated with autosomal recessive Stargardt disease (STGD1). Its presence explained >40% of monoallelic ABCA4 carriers in two separate STGD1 cohorts. Penetrance was estimated to be less than 5% based on expected incidence of Asn1868Ile combinations with severe ABCA4 mutations and estimated prevalence of cases due to these combinations in a STGD1 cohort.
Sharon lab, Hadassah-Hebrew University Medical Center	RCV001002812	SCV001160826	likely pathogenic	Stargardt disease	2019-06-23	no assertion criteria provided	research