ClinVar Miner

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

gnomAD frequency: 0.00024  dbSNP: rs61752424
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, Univ. Regensburg,Univ. Regensburg RCV000408481 SCV000281872 likely pathogenic Severe early-childhood-onset retinal dystrophy 2016-01-01 criteria provided, single submitter clinical testing
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 Disorders 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.
Invitae RCV000085592 SCV001732414 benign not provided 2021-12-18 criteria provided, single submitter clinical testing
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.

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