ClinVar Miner

Submissions for variant NM_000033.4(ABCD1):c.796G>A (p.Gly266Arg) (rs128624218)

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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 RCV000723479 SCV000224133 pathogenic not provided 2015-06-02 criteria provided, single submitter clinical testing
Invitae RCV000012051 SCV000754714 pathogenic Adrenoleukodystrophy 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 266 of the ABCD1 protein (p.Gly266Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with adrenoleukodystrophy (PMID: 7849723, 21068741, 21966424, 15192815, 14767898, 15800013, 7825602) and in some of these individuals the variant occurred de novo (PMID: 21700483). ClinVar contains an entry for this variant (Variation ID: 11299). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000012051 SCV000916401 pathogenic Adrenoleukodystrophy 2018-12-18 criteria provided, single submitter clinical testing Variant summary: ABCD1 c.796G>A (p.Gly266Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 148143 control chromosomes (gnomAD). c.796G>A has been reported in the literature in multiple individuals affected with Adrenoleukodystrophy (Fuchs_1994, Ligtenber_1995, Takano_1999, Asheuer_2005, Pan_2005, Guimaraes_2002). These data indicate that the variant is very likely to be associated with disease. One publication reports that mRNA and protein levels are normal for ABCD1-G266R (Guimaraes_2002), although another publication, Kumar_2011, found the ALDP expression level in peripheral blood mononuclear cells in patients had 50-90% expression. Although, the implications of these levels have yet to be functionally assessed. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000012051 SCV000032285 pathogenic Adrenoleukodystrophy 1994-10-01 no assertion criteria provided literature only

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