ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.442A>T (p.Asn148Tyr) (rs1557052362)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000547607 SCV000630008 likely pathogenic Adrenoleukodystrophy 2017-08-09 criteria provided, single submitter clinical testing This sequence change replaces asparagine with tyrosine at codon 148 of the ABCD1 protein (p.Asn148Tyr). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and tyrosine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with adrenomyeloneuropathy (PMID: 15811009). This variant has also been reported to segregate with disease in a family affected with X-linked adrenoleukodystrophy (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Asn148Ser) has been determined to be pathogenic (PMID: 15811009, 7849723, 10480364, 10190819). This suggests that the asparagine residue is critical for ABCD1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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