Submissions for variant NM_000033.4(ABCD1):c.854G>A (p.Arg285His)

gnomAD frequency: 0.00005  dbSNP: rs782635828

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Raymond Lab, University of Cambridge	RCV000850212	SCV000897750	likely pathogenic	Intellectual disability	2019-02-13	criteria provided, single submitter	research
DASA	RCV002051891	SCV002318951	likely pathogenic	Adrenoleukodystrophy	2022-03-25	criteria provided, single submitter	clinical testing	The c.854G>A;p.(Arg285His) missense change has been observed in affected individual(s) (PMID: 31316545)-PS4_supporting. The variant is located in a mutational hot spot and/or critical and well-established functional domain (ABC_membrane_2) - PM1. This variant is not present in population databases (rs782635828- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic
Mendelics	RCV002249468	SCV002516824	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Laan Lab, Human Genetics Research Group, University of Tartu	RCV002051891	SCV002538604	likely pathogenic	Adrenoleukodystrophy	2021-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002249468	SCV002819908	uncertain significance	not specified	2022-12-30	criteria provided, single submitter	clinical testing	Variant summary: ABCD1 c.854G>A (p.Arg285His) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. At-least three other variants at the same codon, namely p.Arg285Gly, p.Arg285Ser and p.Arg285Pro have been reported in association with Adenoleukodystrophy in the HGMD database, supporting a critical relevance of this location to overall protein function. The variant allele was found at a frequency of 8.2e-06 in 121677 control chromosomes. c.854G>A has been reported in the literature as a likely pathogenic variant in at-least one individual reportedly affected with non-syndromic Intellectual Disability (ID) and additional clinical features seemingly unrelated to X-linked Adenoleukodystrophy, namely right sided schizencephaly and polymicrogyria of right cerebral hemispheres, polycystic malfunctioning kidney, bilateral congenital cataracts and focal epilepsy (Sanchis-Juan_2019). The affected maternal uncle of this proband (Developmental delay, epilepsy, dysmorphic features) harbored a different variant in a gene located in chromosome 1 (SLC2A1 NM_006516.2:c.107C>T, NP_006507:p.Pro36Leu), that the authors classified as likely pathogenic. In the absence of additional biochemical findings, these report(s) do not provide unequivocal conclusions about association of the variant as segregating with X-linked Adrenoleukodystrophy in this reported family. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (LP, n=3; VUS, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.