ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.1390C>T (p.Arg464Ter) (rs128624221)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Institute Rare Disease Group, Broad Institute RCV000012054 SCV001164369 likely pathogenic Adrenoleukodystrophy 2018-12-03 criteria provided, single submitter research The hemizygous p.Arg464Ter variant in ABCD1 was identified by our study in one individual with adrenoleukodystrophy. The p.Arg464Ter variant in ABCD1 has been reported in 1 individual with adrenoleukodystrophy (PMID: 8040304), and was absent from large population studies. This variant has also been reported pathogenic by OMIM in ClinVar (Variation ID: 11302). This nonsense variant leads to a premature termination codon at position 464, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCD1 gene is an established disease mechanism in autosomal recessive adrenoleukodystrophy. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PVS1 (Richards 2015).
Illumina Clinical Services Laboratory,Illumina RCV000012054 SCV001451528 pathogenic Adrenoleukodystrophy 2020-05-28 criteria provided, single submitter clinical testing The ABCD1 c.1390C>T (p.Arg464Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. Across a selection of the available literature, this variant has been identified in at least six unrelated individuals with X-linked adrenoleukodystrophy, including five hemizygous males and one heterozygous female (Kemp et al. 2001; Pan et al. 2005; Asheuer et al. 2005; Wang et al. 2011; Horn et al. 2013). The phenotypes of the males included childhood cerebral adrenoleukodystrophy and adult-onset adrenomyeloneuropathy and the female had a phenotype of adrenomyeloneuropathy, and both maternal and de novo inheritance was observed (Pan et al. 2005; Asheuer et al. 2005; Wang et al. 2011; Horn et al. 2013). Control data are unavailable for the p.Arg464Ter variant, and it is absent from the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the p.Arg464Ter variant is classified as pathogenic for X-linked adrenoleukodystrophy.
Invitae RCV000012054 SCV001578275 pathogenic Adrenoleukodystrophy 2020-05-21 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg464*) in the ABCD1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with X-linked adrenoleukodystrophy (PMID: 8040304, 23419472, 16087056, 24480483, 21700483). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11302). Loss-of-function variants in ABCD1 are known to be pathogenic (PMID: 11748843). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012054 SCV000032288 pathogenic Adrenoleukodystrophy 1994-08-01 no assertion criteria provided literature only

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