Submissions for variant NM_000350.3(ABCA4):c.161G>A (p.Cys54Tyr)

gnomAD frequency: 0.00004  dbSNP: rs150774447

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	RCV000210980	SCV000267673	likely pathogenic	Severe early-childhood-onset retinal dystrophy		criteria provided, single submitter	research	identified in compound heterozygous state in affected individual/s with macular isease
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000210980	SCV000281799	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085408	SCV000321323	pathogenic	not provided	2024-01-10	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: 31429209, 32531858, 33706644, 35456422, 10612508, 25910913, 9973280, 25082885, 25472526, 19217903, 17325179, 14517951, 26527198, 28118664, 30609409, 29925512, 28559085, 31397521, 31980526, 33369172, 35753512, 31963381)
Eurofins Ntd Llc (ga)	RCV000085408	SCV000336475	pathogenic	not provided	2016-12-05	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826094	SCV000967596	likely pathogenic	Stargardt disease	2017-11-22	criteria provided, single submitter	clinical testing	The p.Cys54Tyr (NM_000350.2 c.161G>A) variant in ABCA4 has been reported in at l east 6 compound heterozygotes, 1 homozygote, and 6 individuals without a second pathogenic variant listed, all who had ABCA4-associated retinal degenerations or Stargardt disease (Lewis 1999, Zhang 1999, Aleman 2007, Cella 2009, Fujinami 20 13, Alipati 2014, and Zhao 2015). This variant also segreagated with disease in 3 individuals. This variant has been reported in ClinVar (Variation ID#99065) an d has been identified in 0.007% (9/126642) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1507744 47). Although this variant has been seen in the general population, its frequenc y is low enough to be consistent with a recessive carrier frequency. Computation al prediction tools and conservation analysis suggest that the p.Cys54Tyr varian t may impact the protein, though this information is not predictive enough to de termine pathogenicity. In summary, although additional studies are required to f ully establish its clinical significance, the p.Cys54Tyr variant is likely patho genic for Stargardt disease in an autosomal recessive manner based on its occurr ence in individuals with this disease. ACMG/AMP Criteria applied: PM3_Strong; PM 2; PP1; PP3 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085408	SCV001211642	pathogenic	not provided	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 54 of the ABCA4 protein (p.Cys54Tyr). This variant is present in population databases (rs150774447, gnomAD 0.007%). This missense change has been observed in individual(s) with Stargardt disease (PMID: 10612508, 10634594, 11726554, 11846518, 19074458). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 99065). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000085408	SCV004124083	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	ABCA4: PM3:Very Strong, PP1:Strong, PM2, PM5, PP3, PS3:Supporting
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004815079	SCV005073137	likely pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005031583	SCV005656566	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-04-28	criteria provided, single submitter	clinical testing
Retina International	RCV000085408	SCV000117545	not provided	not provided		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV004529882	SCV004720354	pathogenic	ABCA4-related disorder	2024-01-23	no assertion criteria provided	clinical testing	The ABCA4 c.161G>A variant is predicted to result in the amino acid substitution p.Cys54Tyr. This variant has been reported in the compound heterozygous and homozygous states in many individuals with Stargardt disease and other ABCA4-related retinal disorders (Birch et al. 2001. PubMed ID: 11846518; Zhao et al. 2015. PubMed ID: 25472526; Stone et al. 2017. PubMed ID: 28559085; Fujinami et al. 2019. PubMed ID: 29925512; Lynn et al. 2023. PubMed ID: 36672815) and has been observed to segregate with disease in at least two large families (Zhang et al. 1999. PubMed ID: 10612508; Papaioannou et al. 2000. PubMed ID: 10634594). An in vitro splicing assay demonstrated that this variant has a "moderately severe" impact at the adjacent canonical acceptor site, leading to increased exon-skipping relative to wild type (Fadaie et al. 2019. PubMed ID: 31397521). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD. An additional missense variant at the same amino acid (p.Cys54Gly) has also been reported in patients with ABCA4-related disease (Özgül et al. 2004. PubMed ID: 15108289; Schulz et al. 2017. PubMed ID: 28118664). Taken together, this variant is interpreted as pathogenic.