ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.1900G>A (p.Ala634Thr) (rs782041940)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000488080 SCV000333612 uncertain significance not provided 2015-08-18 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000488080 SCV000575665 likely pathogenic not provided 2016-09-30 criteria provided, single submitter clinical testing
Invitae RCV000633484 SCV000754717 uncertain significance Adrenoleukodystrophy 2017-11-01 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 634 of the ABCD1 protein (p.Ala634Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ABCD1-related disease. ClinVar contains an entry for this variant (Variation ID: 282253). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Johns Hopkins Genomics,Johns Hopkins University RCV000633484 SCV000992324 uncertain significance Adrenoleukodystrophy 2019-03-28 criteria provided, single submitter clinical testing This ABCD1 variant is absent from large population datasets and has not been reported in the literature, to our knowledge. There are conflicting interpretations of the pathogenicity of this variant in ClinVar. One submitter classifies it as likely pathogenic and two as a variant of uncertain clinical significance. Two bioinformatic tools queried predict that this substitution would be damaging, and the alanine residue at this position is highly evolutionarily conserved across all species assessed. Bioinformatic analysis predicts that this variant may create a potential cryptic splice site, however, its effect on splicing has not been studied experimentally to our knowledge. The clinical significance of c.1900G>A is uncertain at this time.

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