Submissions for variant NM_000350.3(ABCA4):c.6079C>T (p.Leu2027Phe)

gnomAD frequency: 0.00018  dbSNP: rs61751408

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000008332	SCV000281947	pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085785	SCV000329049	pathogenic	not provided	2022-09-29	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with decreased ATPase function of the protein, reduced expression compared to wild-type, and abnormal localization to the endoplasmic reticulum (Biswas et al., 2000; Garces 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: 9666097, 11527935, 11702214, 29884405, 29701254, 29310964, 31429209, 32531858, 33706644, 34795310, 34946930, 35456422, 23695285, 19074458, 24713488, 14517951, 9973280, 11328725, 11726554, 10396622, 10090887, 15161829, 29555955, 29847635, 30609409, 30093795, 30060493, 29126757, 30563929, 27820952, 28559085, 32845050, 9054934, 31589614, 32810830, 33546218, 11123914, 29925512)
Eurofins Ntd Llc (ga)	RCV000085785	SCV000700895	pathogenic	not provided	2018-06-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763438	SCV000894205	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2018-10-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000826132	SCV000967648	pathogenic	Stargardt disease	2016-11-10	criteria provided, single submitter	clinical testing	The p.Leu2027Phe variant in ABCA4 has been reported in over 30 individuals with Stargardt disease, including 28 compound heterozygous and 3 homozygous individua ls (Allikmets 1997, Bertelsen 2014, Heathfield 2013, Fujinami 2013). Of note, t he individuals homozygous for this variant presented with a later onset and mild er phenotype (Fujinami 2013, Heathfield 2013). The variant has been identified i n 23/66736 of European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs61751408). Although this variant has been seen in the general population, its frequency is low enough to be consistent wit h a recessive carrier frequency. In vitro functional studies provide some evide nce that the p.Leu2027Phe variant may impact protein function (Biswas 2000). In summary, this variant meets criteria to be classified as pathogenic for Stargard t disease in an autosomal recessive manner based upon observation in patients wi th this disease and functional evidence.
Invitae	RCV000085785	SCV001235490	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2027 of the ABCA4 protein (p.Leu2027Phe). This variant is present in population databases (rs61751408, gnomAD 0.03%). This missense change has been observed in individuals with Stargardt disease (PMID: 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7882). 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%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 29847635). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074885	SCV001240489	pathogenic	Retinal dystrophy	2019-08-12	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085785	SCV001247598	pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000008333	SCV001440311	pathogenic	Cone-rod dystrophy 3	2019-01-01	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000085785	SCV001448776	pathogenic	not provided	2018-05-11	criteria provided, single submitter	clinical testing
Institute of Medical Molecular Genetics, University of Zurich	RCV000008332	SCV001548038	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2021-01-30	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV000008332	SCV002503687	pathogenic	Severe early-childhood-onset retinal dystrophy	2019-11-23	criteria provided, single submitter	clinical testing	This sequence change is predicted to replace leucine with phenylalanine at codon 2027 of the ABCA4 protein (p.Leu2027Phe). The leucine residue is highly conserved (100 vertebrates, UCSC), and located in the cytoplasmic ATP-binding cassette (ABC) transporter 2 domain. There is a small physicochemical difference between leucine and phenylalanine. The variant is present in a large population cohort at a frequency of 0.02%, which is consistent with recessive carrier frequency (rs61751408, 56/282,804 alleles, 0 homozygotes in gnomAD v2.1.1 - PM2). It is a recurrent variant that has been identified as compound heterozygous or homozygous in multiple Stargardt disease patients, with homozygous cases demonstrating a milder phenotype (PMID: 9054934, 23695285, 23769331 - PM3_VeryStrong). The missense change significantly reduces the ATPase function of the ABC transporter domain in multiple in vitro functional assays (PMID: 11017087, 11123914 - PS3). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (7/7 algorithms - PP3). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC . Following criteria are met: PM3_VeryStrong, PS3, PM2, PP3.
Mendelics	RCV002247268	SCV002517480	pathogenic	Age related macular degeneration 2	2022-05-04	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000008332	SCV002557496	pathogenic	Severe early-childhood-onset retinal dystrophy	2022-06-24	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Stargardt disease 1 (MIM#248200). (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 leucine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2 & v3) for a recessive condition (74 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ABC transporter domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with autosomal recessive Stargardt disease (ClinVar, PMID: 23695285). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000008332	SCV000028540	pathogenic	Severe early-childhood-onset retinal dystrophy	2003-06-01	no assertion criteria provided	literature only
OMIM	RCV000008333	SCV000028541	pathogenic	Cone-rod dystrophy 3	2003-06-01	no assertion criteria provided	literature only
Retina International	RCV000085785	SCV000117927	not provided	not provided		no assertion provided	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000085785	SCV001551440	pathogenic	not provided		no assertion criteria provided	clinical testing	The ABCA4 p.Leu2027Phe variant was identified in 44 of 428 proband chromosomes (frequency: 0.103) from individuals or families with Stargardt Disease, Cone-Rod dystrophy or ABCA4-Associated Retinopathies (Maugeri_1999_PMID:10090887; Bertelsen_2014_PMID:24713488; Heathfield_2013_PMID:23695285, Fishman_2003_PMID:12796258). The variant was identified in dbSNP (ID: rs61751408) and in ClinVar (classified as pathogenic by EGL Genetic Diagnostics, Fulgent Genetics, GeneDx and Institute of Human Genetics, Univ. Regensburg). The variant was also identified in control databases in 56 of 282804 chromosomes at a frequency of 0.000198 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 45 of 129122 chromosomes (freq: 0.000349), African in 8 of 24968 chromosomes (freq: 0.00032), Other in 1 of 7222 chromosomes (freq: 0.000139) and Latino in 2 of 35436 chromosomes (freq: 0.000056); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Leu2027 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein. However, in vitro functional studies of the L2027F variant have demonstrated biochemical defects leading to lower protein functionality and altered ATPase function (Sun_2000_PMID: 11017087; Biswas_2000_PMID: 11123914). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.