Submissions for variant NM_000350.3(ABCA4):c.3758C>T (p.Thr1253Met)

gnomAD frequency: 0.00024  dbSNP: rs61752424

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000085592	SCV000968530	likely benign	not provided	2021-02-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25082829, 11726554, 26593885, 22661473, 23755871, 11385708, 19217903, 22076985, 28118664, 29925512, 31589614)
Blueprint Genetics	RCV001075720	SCV001241348	uncertain significance	Retinal dystrophy	2019-05-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001101851	SCV001258492	uncertain significance	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085592	SCV001732414	benign	not provided	2024-01-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317087	SCV004020573	uncertain significance	not specified	2023-06-12	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.3758C>T (p.Thr1253Met) 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 0.00043 in 251346 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in ABCA4 causing Retinitis Pigmentosa (0.00043 vs 0.0014), allowing no conclusion about variant significance. c.3758C>T has been reported in the literature as a non-informative genotype in cis with a different variant in the ABCA4 gene in cohorts with multifactorial age-related macular degeneration (AMD); bulls-eye maculopathy; inherited retinal disease and/or Stargardt disease (example, Shroyer_2001, Michaelides_2007, Zampaglione_2020, Sciezynska_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Retinitis Pigmentosa or ABCA4-related opthalmological disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18024811, 26593885, 11726554, 32037395). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=2; VUS, n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Retina International	RCV000085592	SCV000117730	not provided	not provided		no assertion provided	not provided
Reproductive Health Research and Development, BGI Genomics	RCV000408481	SCV001142301	uncertain significance	Severe early-childhood-onset retinal dystrophy	2020-01-06	no assertion criteria provided	curation	NM_000350.2:c.3758C>T in the ABCA4 gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been reported previously in individuals with fundus flavimaculatus or retinal disorders (PMID: 11385708, 23755871). Riveiro-Alvarez reported a patient with autosomal recessive Retinal Dystrophies habors c.[3758C>T; 5582G>A];[3943C>T] (PMID: 23755871). In addition, Cella et al. reported T1253M compound heterozygous with G1961E in a bull's eye maculopathy patient (PMID: 19217903). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT. We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: PM3; PP3, PP4.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000085592	SCV001552360	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ABCA4 p.Thr1253Met variant was identified in 6 of 1414 proband chromosomes (frequency: 0.0042) from individuals or families with ABCA4-related conditions (Stargardt disease 1, autosomal recessive retinitis pigmentosa, cone-rod dystrophy), however this variant has often been found in cis with the pathogenic p.G1961E variant, therefore it is unclear how this variant contributes to disease (Burke_2012_PMID:22661473; Shroyer_2001_PMID:11726554; Rosenberg_2007_PMID:17982420; Valverde_2005_PMID:16917483; Cella_2009_PMID:19217903; Riveiro-Alvarez_2013_PMID:23755871). The variant was identified in dbSNP (ID: rs61752424) and ClinVar (classified as likely benign by GeneDx, likely pathogenic by Institute of Human Genetics University Regensburg for Stargardt disease 1 and uncertain significance by Reproductive Health Research and Development BGI Genomics). The variant was identified in control databases in 113 of 282758 chromosomes (1 homozygous) at a frequency of 0.0003996 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 93 of 10358 chromosomes (freq: 0.008979), European (non-Finnish) in 18 of 129090 chromosomes (freq: 0.000139) and South Asian in 2 of 30614 chromosomes (freq: 0.000065), but was not observed in the African, Latino, East Asian, European (Finnish), or Other populations. The p.Thr1253 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. 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. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV001101851	SCV004744363	likely benign	ABCA4-related disorder	2021-06-30	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).