ClinVar Genomic variation as it relates to human health

This variant is interpreted as a variant of uncertain significance, for Adrenoleukodystrophy, in X-linked Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:8651290) (PMID:17542813) (PMID:21966424).

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser606 amino acid residue in ABCD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCD1 function (PMID: 8651290, 17542813). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 218422). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 606 of the ABCD1 protein (p.Ser606Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with adrenoleukodystrophy and/or adrenomyeloneuropathy (PMID: 8651290, 21700483, 21966424). In at least one individual the variant was observed to be de novo.

ABCD1, c.1816T>C, p.Ser606Pro, Hemizygous, Uncertain SignificanceThe ABCD1 p.Ser606Pro variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was identified in dbSNP (ID: rs201774661) as Conflicting intepretations of pathogencity (Adrenoleukodystrophy), ClinVar (Conflicting interpretations of pathogenicity. Classified as likely pathogenic by Swiss Institute of Bioinformatics in 2018. Likely benign by Children's Hospital of Philadelphia in 2015, Illumina in 2016. Benign by Mendelics in 2019), and  LOVD 3.0 (Two entries, one as VUS, one unclassified)  databases. The variant was identified in control databases in 120 of 163177 chromosomes at a frequency of 0.0007354 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 25 of 13442 chromosomes (freq: 0.00186), East Asian in 11 of 12400 chromosomes (freq: 0.000887), European (Finnish) in 12 of 15417 chromosomes (freq: 0.000778), European (non-Finnish) in 53 of 71204 chromosomes (freq: 0.000744), Ashkenazi Jewish in 4 of 6757 chromosomes (freq: 0.000592), Latino in 11 of 24333 chromosomes (freq: 0.000452), Other in 1 of 4316 chromosomes (freq: 0.000232), and South Asian in 3 of 15308 chromosomes (freq: 0.000196). However, the variant was only identified in females and in no males; ABCD1 is associated with X-linked recessive adrenomyeloneuropathy. The c.1816T>C variant was reported in an 11-year-old male of Indian origin with adolescent onset cerebral andrenomyeloneuropathy. Western blot indicated that the p.Ser606Pro variant resulted in no ALDP protein expression in the patient's peripheral blood mononuclear cells. (Kumar_2011_PMID:21966424) The c.1816T>C variant was identified in a Chinese patient with adrenoleukodystrophy, who was also found to have c.1028G>T and c.1814C>T variants. The proband's mother was found to be heterozygous for the c.1028G>T variant, and homozygous for the c.1814C>T and c.1816T>C variants. (Niu_2013_PMID:23566833) The p.Ser606 residue is conserved in mammals but not in more distantly related organisms, and 8 of 9 computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster, DANN, MT, HATHMM, MetaLR, Revel) 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.Disease Information: X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and the adrenal cortex. Adrenoleukodystrophy results in the apparent defect in peroxisomal beta oxidation and the accumulation of the saturated very long chain fatty acids (VLCFA) in all tissues of the body (OMIM: 300100). The manifestations of the disorder occur primarily in the adrenal cortex, the myelin of the central nervous system, and the Leydig cells of the testes (OMIM: 300100).  Adrenomyeloneuropathy (AMN) manifests most commonly in an individual in his twenties or middle age as progressive stiffness and weakness of the legs, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function; all symptoms are progressive over decades. (Verbatim, GeneReviews) Clinical features include progressive neurodegeneration, cognitive decline, loss of speech, dementia, bulbar palsy, seizures, pararesis, spasticity, incoordination, ataxia, white matter abnormalities, sensory loss, and cerebral demyelination and inflammation. (OMIM: 300100)Familial Risk: Adrenoleukodystrophy is inherited in an X-linked recessive manner. Each male offspring of an individual with a variant has a 50% chance of inheriting the variant. At conception, the female siblings of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers.