Submissions for variant NM_000350.3(ABCA4):c.4234C>T (p.Gln1412Ter)

gnomAD frequency: 0.00001  dbSNP: rs61750137

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV000408549	SCV000281882	pathogenic	Severe early-childhood-onset retinal dystrophy	2016-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000085616	SCV000511893	pathogenic	not provided	2021-12-22	criteria provided, single submitter	clinical testing	Nonsense 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; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25640233, 25283059, 10090887, 25525159, 24713488, 29555955, 29847651, 30204727, 29925512, 28559085, 28118664, 31574917, 29854428, 26806561, 26103963, 31766579)
Blueprint Genetics	RCV001074847	SCV001240448	pathogenic	Retinal dystrophy	2019-07-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000085616	SCV001249458	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	ABCA4: PM3:Very Strong, PVS1, PM2
Labcorp Genetics (formerly Invitae), Labcorp	RCV000085616	SCV001387016	pathogenic	not provided	2024-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1412*) 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). This variant is present in population databases (rs61750137, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with various forms of retinal disease (PMID: 10090887, 24713488, 25283059, 28559085, 29847651). ClinVar contains an entry for this variant (Variation ID: 99263). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000085616	SCV001447344	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV000408549	SCV002058182	pathogenic	Severe early-childhood-onset retinal dystrophy	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000007, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000099263, PMID:10090887). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000408549	SCV002102454	pathogenic	Severe early-childhood-onset retinal dystrophy	2022-02-18	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous with NM_000350.3:c.4773+3A>G._x000D_ Criteria applied: PVS1, PM3_VSTR, PM2_SUP
MGZ Medical Genetics Center	RCV000408549	SCV002581170	pathogenic	Severe early-childhood-onset retinal dystrophy	2022-07-26	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490742	SCV002801087	pathogenic	Cone-rod dystrophy 3; Age related macular degeneration 2; Severe early-childhood-onset retinal dystrophy; Retinitis pigmentosa 19	2024-05-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155072	SCV003844720	pathogenic	Retinitis pigmentosa	2023-02-01	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.4234C>T (p.Gln1412X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 4e-06 in 251372 control chromosomes (gnomAD). c.4234C>T has been reported in the literature in individuals affected with various forms of retinal disease (example: Maugeri_1999, Bertelsen_2014, Duncker_2015). These data indicate that the variant is very likely to be associated with disease. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001074847	SCV005072533	pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Retina International	RCV000085616	SCV000117755	not provided	not provided		no assertion provided	not provided