Submissions for variant NM_000350.3(ABCA4):c.6146del (p.Lys2049fs)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174687	SCV001337922	pathogenic	Stargardt disease	2020-01-08	criteria provided, single submitter	clinical testing	Variant summary: ABCA4 c.6146delA (p.Lys2049ArgfsX12) 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. The variant was absent in 251348 control chromosomes (gnomAD). c.6146delA has been reported in the literature in individuals (particularly Korean) affected with Stargardt disease (e.g. Sung_2018, Joo_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV001250529	SCV001425336	pathogenic	Severe early-childhood-onset retinal dystrophy	2020-01-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003727942	SCV004540277	pathogenic	not provided	2024-05-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys2049Argfs*12) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Stargardt disease (PMID: 29975949, 31814693). ClinVar contains an entry for this variant (Variation ID: 917611). For these reasons, this variant has been classified as Pathogenic.

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