ClinVar Miner

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

dbSNP: rs128624218
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000723479 SCV000224133 pathogenic not provided 2015-06-02 criteria provided, single submitter clinical testing
Invitae RCV000012051 SCV000754714 pathogenic Adrenoleukodystrophy 2023-08-24 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 266 of the ABCD1 protein (p.Gly266Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adrenoleukodystrophy (PMID: 7825602, 7849723, 14767898, 15192815, 15800013, 21068741, 21700483, 21966424). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 11299). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCD1 protein function. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Revvity Omics, Revvity Omics RCV000723479 SCV002018739 pathogenic not provided 2022-02-17 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000012051 SCV002045814 pathogenic Adrenoleukodystrophy 2021-11-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV002415409 SCV002678028 pathogenic Inborn genetic diseases 2017-07-10 criteria provided, single submitter clinical testing The p.G266R pathogenic mutation (also known as c.796G>A), located in coding exon 1 of the ABCD1 gene, results from a G to A substitution at nucleotide position 796. The glycine at codon 266 is replaced by arginine, an amino acid with dissimilar properties. This mutation was observed to segregate with disease in one large family in France (Fuchs S et al. Hum. Mol. Genet., 1994 Oct;3:1903-5). It has also been described as a de novo occurrence in multiple unrelated probands (Wang Y et al. Mol. Genet. Metab., 2011 Jun;104:160-6; Ohkuma Y et al. Neuroophthalmology, 2014 Oct;38:331-335). Furthermore, multiple different phenotypes have been observed among mutation carriers (Kumar N et al. PLoS ONE, 2011 Sep;6:e25094). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000012051 SCV003919859 pathogenic Adrenoleukodystrophy 2021-03-30 criteria provided, single submitter clinical testing ABCD1 NM_000033.3 exon 1 p.Gly266Arg (c.796G>A): This variant has been reported in the literature in several individuals with adrenoleukodystrophy, with one reported to be de novo (Fuchs 1994 PMID:7849723, Ligtenberg 1995 PMID:7825602, Pan 2004 PMID:14767898, Huang 2004 PMID:15192815, Asheuer 2005 PMID:15800013, Shimozawa 2011 PMID:21068741, Kumar 2011 PMID:21966424, Wang 2011 PMID:21700483). This variant is not present in large control databases but is present in ClinVar, with multiple labs classifying this variant as pathogenic (Variation ID:11299). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic based on the data above.
GeneDx RCV000723479 SCV004023455 pathogenic not provided 2022-03-21 criteria provided, single submitter clinical testing Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20661612, 11748843, 16415970, 17504626, 34826210, 21966424, 21068741, 15800013, 14767898, 7825602, 15192815, 10190819, 12175782, 16087056, 21300044, 23419472, 21700483, 31227335, 31418856, 34997422, 31069529, 27928321, 7849723)
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV000012051 SCV004047778 pathogenic Adrenoleukodystrophy criteria provided, single submitter clinical testing The c.796G>A (p.Gly266Arg) missense variant has been reported in multiple individuals affected with adrenoleukodystrophy (Shimozawa et al., 2011; Kumar et al., 2011) and in some of these individuals the variant occurred de novo (Wang et al., 2011). The p.Gly266Arg variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been submitted to ClinVar as Pathogenic. The amino acid Gly at position 266 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Gly266Arg in ABCD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV003483432 SCV004231772 benign not specified 2023-05-12 criteria provided, single submitter research
OMIM RCV000012051 SCV000032285 pathogenic Adrenoleukodystrophy 1994-10-01 no assertion criteria provided literature only
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001358196 SCV001553869 pathogenic X-linked spondyloepimetaphyseal dysplasia no assertion criteria provided clinical testing The ABCD1 p.Gly266Arg variant was identified in 34 of 1408 proband chromosomes (frequency: 0.024) from individuals or families with X-linked adrenoleukodystrophy (Asheuer 2005, Guimaraes 2002, Horn 2013, Kumar 2011, Lan 2011, Matsukawa 2010, Shimozawa 2011, Wang 2011). The variant was also found in case study by Ohkuma (2014) in 10-year-old male with childhood cerebral X-linked ALD. The variant was identified in dSNP (rs128624218) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, OMIM and EGL genetic Diagnistics), the ALD Mutation Database (as pathogenic, identified in 33 ALD patients; normal ALDP level in patient cells but non-functional), and LOVD. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant did not have any effect on protein stability in experimental study by Kawaguchi (2016) indicating that this amino acid residue is likely critical for the protein function as it was one of the most common ABCD1 mutations seen in patients with ALD in the literature. The p.Gly266 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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