ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.1866-10G>A (rs398123108)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000414732 SCV000109790 pathogenic not provided 2014-11-07 criteria provided, single submitter clinical testing
GeneDx RCV000414732 SCV000491030 pathogenic not provided 2019-08-07 criteria provided, single submitter clinical testing Functional analysis of c.1866-10 G>A found that it results in the creation of an upstream splice acceptor site, leading to abnormal splicing (Kemp et al., 1995; Kumar et al., 2011); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26454440, 9242200, 9846054, 8004093, 31104286, 8535452, 22479560, 28481932, 21966424)
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626568 SCV000747269 likely pathogenic Spastic gait; Spastic paraplegia 2017-01-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000924 SCV001158011 pathogenic not specified 2018-11-14 criteria provided, single submitter clinical testing The ABCD1 c.1866-10G>A variant (rs398123108), is reported in the literature in multiple individuals affected with X-linked adrenoleukodystrophy (Chen 2017, Chu 2015, Kemp 1995, Kumar 2011, Pereira Fdos 2012, ALD Mutation Database). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 92323), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant creates a novel cryptic splice site that is predicted to be the preferred acceptor site for splicing intron 8. This prediction is supported by studies showing an insertion of 8 nucleotides at the beginning of exon 9, resulting in a premature stop codon and a significant reduction in protein production (Kemp 1995, Kumar 2011). Based on available information, the c.1866-10G>A variant is considered to be pathogenic. References: Link to ALD Mutation Database: Chen YH et al. Unmasking adrenoleukodystrophy in a cohort of cerebellar ataxia. PLoS One. 2017 May 8;12(5):e0177296. Chu SS et al. Eight novel mutations in the ABCD1 gene and clinical characteristics of 25 Chinese patients with X-linked adrenoleukodystrophy. World J Pediatr. 2015 Nov;11(4):366-73. Kemp S et al. Two intronic mutations in the adrenoleukodystrophy gene. Hum Mutat. 1995;6(3):272-3. Kumar N et al. Genomic profiling identifies novel mutations and SNPs in ABCD1 gene: a molecular, biochemical and clinical analysis of X-ALD cases in India. PLoS One. 2011;6(9):e25094. Pereira Fdos S et al. Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy. PLoS One. 2012;7(3):e34195.
Johns Hopkins Genomics, Johns Hopkins University RCV000077961 SCV001167282 pathogenic Adrenoleukodystrophy 2019-09-13 criteria provided, single submitter clinical testing This ABCD1 variant has been reported in numerous patients with phenotypes ranging from childhood cerebral adrenoleukodystrophy to adrenomyeloneuropathy. A functional study has confirmed that this variant produces a novel splice acceptor site that adds 8 nucleotides to exon 9 and destroys the native acceptor site. ABCD1 c.1866-10G>A is absent from large population datasets. Four submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. We consider this variant to be pathogenic.
OMIM RCV000077961 SCV000032281 pathogenic Adrenoleukodystrophy 1995-01-01 no assertion criteria provided literature only

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