Submissions for variant NM_000033.4(ABCD1):c.1448C>T (p.Thr483Met)

dbSNP: rs1569541035

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000710399	SCV000840611	uncertain significance	not provided	2018-03-16	criteria provided, single submitter	clinical testing
Invitae	RCV000800638	SCV000940367	pathogenic	Adrenoleukodystrophy	2023-08-04	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 483 of the ABCD1 protein (p.Thr483Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of adrenoleukodystrophy (PMID: 34946879; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 585354). 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.
GeneDx	RCV000710399	SCV001817805	uncertain significance	not provided	2020-01-29	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016)
Genome-Nilou Lab	RCV000800638	SCV002045792	uncertain significance	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907963	SCV004724427	uncertain significance	ABCD1-related condition	2023-12-28	criteria provided, single submitter	clinical testing	The ABCD1 c.1448C>T variant is predicted to result in the amino acid substitution p.Thr483Met. This variant was reported in an individual with abnormal C26:0 levels and C26:0/C22:0 ratios, but without symptoms of X-linked adrenoleukodystrophy (X-ALD). ABCD1 protein expression was also found to be reduced in this individual (VUS02, Table 3, van de Stadt et al. 2021. PubMed ID: 34946879). In another report this variant was identified in a male infant screening positive for X-ALD, however the variant was determined to be maternally-inherited and no family history was reported (Table 1, Priestley et al. 2022. PubMed ID: 35466195). At PreventionGenetics, we have observed this variant in an individual with features consistent with X-ALD (internal data). While this variant has not been reported in gnomAD v2.0, it has recently been reported in 6 heterozygous individuals, including two hemizygotes, in gnomAD v4.0.0 (reported in hg38 as chrX-153737211-C-T). In an ABCD1-specific database, this variant is also listed as uncertain (https://adrenoleukodystrophy.info/mutations-and-variants-in-abcd1#323). While we suspect this variant could be pathogenic, at this time, we interpret its clinical significance as uncertain due to the absence of conclusive functional and genetic evidence.