ClinVar Miner

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

dbSNP: rs128624221
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard 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 Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000012054 SCV001578275 pathogenic Adrenoleukodystrophy 2024-01-21 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. Loss-of-function variants in ABCD1 are known to be pathogenic (PMID: 11748843). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with X-linked adrenoleukodystrophy (PMID: 8040304, 16087056, 21700483, 23419472, 24480483). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11302). For these reasons, this variant has been classified as Pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens RCV000012054 SCV001976944 pathogenic Adrenoleukodystrophy 2021-10-01 criteria provided, single submitter clinical testing PVS1, PM2, PP3
Revvity Omics, Revvity RCV001781250 SCV002018728 pathogenic not provided 2022-02-17 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000012054 SCV002045826 pathogenic Adrenoleukodystrophy 2021-11-07 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV000012054 SCV004024513 pathogenic Adrenoleukodystrophy 2023-06-28 criteria provided, single submitter clinical testing This ABCD1 variant has been reported in multiple unrelated individuals with ABCD1 - related disorders, including as a de novo occurrence. It has also been reported in ClinVar (Variation ID 11302), but is absent from a large population dataset6. This nonsense variant results in a premature stop codon in exon 4 of 10, likely leading to nonsense-mediated decay and lack of protein production. We consider c.1390C>T in ABCD1 to be pathogenic.
PreventionGenetics, part of Exact Sciences RCV003415686 SCV004118413 pathogenic ABCD1-related disorder 2023-04-13 criteria provided, single submitter clinical testing The ABCD1 c.1390C>T variant is predicted to result in premature protein termination (p.Arg464*). This variant has been reported to be causative for X-Linked adrenoleukodystrophy (reported as C1776T in Fanen et al. 1994. PMID: 8040304). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare and has been interpreted as pathogenic/likely pathogenic by multiple submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/11302/). Nonsense variants in ABCD1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV000012054 SCV004242462 pathogenic Adrenoleukodystrophy 2023-12-13 criteria provided, single submitter clinical testing Criteria applied: PVS1,PS4,PS2_MOD,PM2_SUP
OMIM RCV000012054 SCV000032288 pathogenic Adrenoleukodystrophy 1994-08-01 no assertion criteria provided literature only
Natera, Inc. RCV000012054 SCV002084638 pathogenic Adrenoleukodystrophy 2020-11-16 no assertion criteria provided clinical testing

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