Submissions for variant NM_000350.3(ABCA4):c.4537dup (p.Gln1513fs)

dbSNP: rs281865377

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000085645	SCV000490378	pathogenic	not provided	2022-10-17	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26872967, 11527935, 25097154, 18652558, 22968130, 24938718, 29555955, 28041643, 31872526, 32581362, 32619608, 31429209, 32531858, 34758253, 29925512)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004999	SCV001164557	pathogenic	Cone-rod dystrophy 3	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Gln1513ProfsTer42 variant in ABCA4 was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with cone-rod dystrophy. The p.Gln1513ProfsTer42 variant in ABCA4 has not been previously reported in individuals with cone-rod dystrophy but has been identified in 0.004031% (6/148860) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs281865377). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 1513 and leads to a premature termination codon 42 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ABCA4 gene is an established disease mechanism in autosomal recessive cone-rod dystrophy, and this is a loss of function variant. The presence of this variant in combination with a likely pathogenic variant and in an individual with cone-rod dystrophy increases the likelihood that the p.Gln1513ProfsTer42 variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for cone-rod dystrophy in an autosomal recessive manner based on the predicted impact of the variant and the presence of a likely pathogenic variant in trans. ACMG/AMP Criteria applied: PM2, PVS1, PM3_Supporting (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085645	SCV001211638	pathogenic	not provided	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1513Profs*42) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with inherited retinal dystrophy (PMID: 11527935, 28041643). ClinVar contains an entry for this variant (Variation ID: 99292). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001074410	SCV001239992	pathogenic	Retinal dystrophy	2019-08-11	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085645	SCV001448008	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Retina International	RCV000085645	SCV000117784	not provided	not provided		no assertion provided	not provided
Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	RCV000210298	SCV000259088	likely pathogenic	Severe early-childhood-onset retinal dystrophy	2015-01-22	no assertion criteria provided	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504708	SCV000598978	pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504962	SCV000598979	likely pathogenic	Macular dystrophy	2015-01-01	no assertion criteria provided	research
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000678509	SCV000804579	pathogenic	Retinitis pigmentosa 19	2016-09-01	no assertion criteria provided	clinical testing
Sharon lab, Hadassah-Hebrew University Medical Center	RCV002267726	SCV001160845	pathogenic	Cone-rod dystrophy	2019-06-23	no assertion criteria provided	research
Genomics England Pilot Project, Genomics England	RCV000678509	SCV001760053	likely pathogenic	Retinitis pigmentosa 19		no assertion criteria provided	clinical testing
Ophthalmo-Genetics Lab, Instituto de Oftalmologia Conde de Valenciana	RCV000210298	SCV005047019	pathogenic	Severe early-childhood-onset retinal dystrophy		no assertion criteria provided	research
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074410	SCV005071233	pathogenic	Retinal dystrophy	2023-01-01	no assertion criteria provided	clinical testing