Submissions for variant NM_000033.4(ABCD1):c.896A>G (p.His299Arg)

dbSNP: rs782430461

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001034913	SCV001198216	uncertain significance	Adrenoleukodystrophy	2021-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with arginine at codon 299 of the ABCD1 protein (p.His299Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with ABCD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Human Genetics Laboratory, Faculty of Medicine of Tunis	RCV001843369	SCV002102484	uncertain significance	not specified	2021-04-01	criteria provided, single submitter	research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001034913	SCV002767615	uncertain significance	Adrenoleukodystrophy	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. There are multiple Loss of Function variants along the ABCD1 gene (Decipher). (N) 0104 - Dominant Negative is a mechanism of disease for this gene. Mutant adrenoleukodystrophy protein (ALDP) has been hypothesized to exert a dominant negative effect through the formation of non-functional heterodimers with the wild type ALDP (PMID: 11063720). (N) 0109 - This gene is known to be associated with X-linked recessive disease. However, female carriers have been also reported to be symptomatic (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from histidine to arginine (exon 1). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD v3 (66 Heterozygotes, 26 Hemizygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and very highly conserved with a minor amino acid change. (P) 0600 - Variant is located in an annotated domain or motif. The variant is in the ABCD1 Transmembrane-1 Domain (Protein Data Bank). (N) 0710 - Comparable variants have some previous evidence for being benign. The p.His299Tyr variant was previously identified in 1 individual with adrenoleukodystrophy but was classified as a false positive due to the number of hemizygotes present in the population. (B) 0808 - Previous reports of pathogenicity are conflicting. The variant has been classified as a Variant of Uncertain Significance in ClinVar and LOVD but has also been classified as Pathogenic in the ALD mutation database. (N) 0905 - No segregation evidence has been identified for this variant in the literature. (N) 1007 - No published functional evidence has been identified for this variant literature. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Fulgent Genetics, Fulgent Genetics	RCV001034913	SCV002782211	uncertain significance	Adrenoleukodystrophy	2021-12-22	criteria provided, single submitter	clinical testing
Daryl Scott Lab, Baylor College of Medicine	RCV001034913	SCV005871118	uncertain significance	Adrenoleukodystrophy	2024-01-01	criteria provided, single submitter	clinical testing	PM2, PP3