ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.761C>T (p.Thr254Met) (rs1131691743)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493818 SCV000582737 likely pathogenic not provided 2016-07-22 criteria provided, single submitter clinical testing The T254M variant has been reported in individuals who had biochemical and/or clinical features consistent with ALD (Horn et al., 2013; Krasermann et al., 1996; Bargiela et al., 2014). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T254M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be completely excluded.
Invitae RCV000633477 SCV000754709 pathogenic Adrenoleukodystrophy 2019-05-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 254 of the ABCD1 protein (p.Thr254Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as de novo in two independent individuals affected with adrenoleukodystrophy and in a Norwegian kindred with the same condition (PMID: 8566952, 23419472, Invitae). ClinVar contains an entry for this variant (Variation ID: 430026). 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 and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.

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