Submissions for variant NM_000350.3(ABCA4):c.2894A>G (p.Asn965Ser)

gnomAD frequency: 0.00007  dbSNP: rs201471607

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408500	SCV000281855	pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000413621	SCV000490371	pathogenic	not provided	2022-06-16	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with partial misfolding of the protein with mislocalization and low ATPase activity (Molday et al., 2018); 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: 9054934, 27739528, 28446513, 27939946, 28118664, 22968130, 25356976, 24453473, 24713488, 26780318, 28327576, 28704108, 29126757, 24097981, 21226556, 30204727, 29925512, 30718709, 30093795, 31456290, 32845050, 32845068, 32531858, 33732702, 32619608, 33090715, 33691693, 33301772, 33261146, 32244552, 17982420, 28559085, 29145636)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413621	SCV001201574	pathogenic	not provided	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 965 of the ABCA4 protein (p.Asn965Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with ABCA4-related disease and/or Stargardt disease (PMID: 17982420, 25356976, 27739528, 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236096). 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 have shown that this missense change affects ABCA4 function (PMID: 22735453, 24097981, 29145636). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074886	SCV001240490	pathogenic	Retinal dystrophy	2019-08-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000413621	SCV001249473	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	ABCA4: PM3:Very Strong, PM1, PM2, PM5:Supporting, PS3:Supporting
Molecular Genetics, Royal Melbourne Hospital	RCV000408500	SCV002503846	pathogenic	Severe early-childhood-onset retinal dystrophy	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace asparagine with serine at codon 965 of the ABCA4 protein, p.(Asn965Ser). The asparagine residue is moderately conserved (100 vertebrates, UCSC), and is located within the Walker A motif in the ATP binding cassette transporter 1 domain, critical for nucleotide phosphate binding (PMID: 29145636). There is a small physicochemical difference between asparagine and serine. The variant is present in a large population cohort at a frequency of 0.01%, which is consistent with recessive disease (rs201471607, 35/282,722 alleles, 0 homozygotes in gnomAD v2.1). It has been identified in the homozygous state and compound heterozygous with a second pathogenic allele in multiple cases with retinal disorders including Stargadt disease, fundus flavimaculatus, retinitis pigmentosa, cone-rod dystrophy, and Bull's eye maculopathy (PMID: 17982420 , 20647261). Further, a p.Asn965Ser knock-in mouse model recapitulates the phenotype of Stargardt disease patients and Abca4 knockout mice (PMID: 29145636). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/7 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PS3, PM1, PM2, PP3.
3billion, Medical Genetics	RCV000408500	SCV002521702	pathogenic	Severe early-childhood-onset retinal dystrophy	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:29145636). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.78; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000236096). The variant has been reported to be homozygous in at least one similarly affected unrelated individual (PMID: 17982420). Different missense changes at the same codon (p.Asn965Asp, p.Asn965Lys) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000099172, VCV000636146). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Dept Of Ophthalmology, Nagoya University	RCV001074886	SCV004704769	pathogenic	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074886	SCV005070885	pathogenic	Retinal dystrophy	2020-01-01	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796120	SCV005417522	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_VeryStrong+PP3_Moderate
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787490	SCV000926456	pathogenic	Stargardt disease	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787491	SCV000926457	pathogenic	Cone-rod dystrophy	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787492	SCV000926458	pathogenic	Macular dystrophy	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787770	SCV000926775	pathogenic	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Sharon lab, Hadassah-Hebrew University Medical Center	RCV000787490	SCV001160856	pathogenic	Stargardt disease	2019-06-23	no assertion criteria provided	research
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV004558582	SCV005046949	pathogenic	Stargardt disease 3		no assertion criteria provided	research