Submissions for variant NM_000350.3(ABCA4):c.1964T>G (p.Phe655Cys)

gnomAD frequency: 0.00033  dbSNP: rs200692438

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000194199	SCV000223915	likely pathogenic	Cone-rod dystrophy 3; Severe early-childhood-onset retinal dystrophy	2014-10-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408459	SCV000281840	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071977	SCV001237317	pathogenic	not provided	2024-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 655 of the ABCA4 protein (p.Phe655Cys). This variant is present in population databases (rs200692438, gnomAD 0.09%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 21911583, 22229821, 22661472, 29925512). 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: 212727). 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%. For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001075570	SCV001241197	pathogenic	Retinal dystrophy	2019-01-09	criteria provided, single submitter	clinical testing
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV000408459	SCV001573367	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-04-08	criteria provided, single submitter	research	The ABCA4 c.1964T>G variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3-S. Based on this evidence we have classified this variant as Likely Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000408459	SCV002767905	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely pathogenic. The 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), fundus flavimaculatus (MIM #248200), early-onset severe retinal dystrophy (MIM #248200) and retinitis pigmentosa 19 (MIM #601718). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 31522899). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (110 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 ABC2 membrane 3 domain (Pfam). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported as likely pathogenic and pathogenic four times in ClinVar in association with ABCA4-related eye disease. It has been reported in at least 10 patients with Stargardt or ABCA4-related eye disease in the literature where a 2nd disease-causing variant was identified in trans (PMIDs: 32821503; 22661472; 29925512; 28118664; 28446513; 21911583; 17296903; 31212395). This variant has also been reported as likely benign (based on case/control frequency data)/VUS (based on ACMG classification guidelines) by the same study (PMID: 28044389). (SP) 0705 - No comparable missene variants have previous evidence for pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV002485297	SCV002791522	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-06-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001071977	SCV003831231	likely pathogenic	not provided	2022-08-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001071977	SCV004036969	likely pathogenic	not provided	2023-09-20	criteria provided, single submitter	clinical testing	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: 17296903, 28118664, 22229821, 31589614, 22661472, 21911583, 29754767, 32619608, 33851411, 29925512, 34954332, 34874912, 32531858, 35119454)
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075570	SCV005072441	likely pathogenic	Retinal dystrophy	2020-01-01	criteria provided, single submitter	clinical testing