ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.1998_1999insGC (p.His667fs) (rs1557055392)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000530996 SCV000629998 likely pathogenic Adrenoleukodystrophy 2017-04-04 criteria provided, single submitter clinical testing This sequence change inserts 2 nucleotides in exon 10 of the ABCD1 mRNA (c.1998_1999insGC), causing a frameshift at codon 667. This creates a premature translational stop signal in the last exon of the ABCD1 mRNA (p.His667Alafs*25). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acids of the ABCD1 protein. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ABCD1-related disease. A missense substitution at this codon (p.His667Asp) has been determined to be pathogenic (PMID: 11748843, 15800013, 17542813). This suggests that the histidine residue is critical for ABCD1 protein function and that its disruption by this variant may also be pathogenic. In summary, this variant is a novel frameshift variant that disrupts that last 79 amino acids of the ABCD1 protein, including a functionally important histidine residue (p.His667). This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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