Submissions for variant NM_000033.4(ABCD1):c.739G>A (p.Ala247Thr)

gnomAD frequency: 0.00001  dbSNP: rs782487174

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633488	SCV000754721	likely pathogenic	Adrenoleukodystrophy	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 247 of the ABCD1 protein (p.Ala247Thr). 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 clinical features of adrenoleukodystrophy (Invitae). ClinVar contains an entry for this variant (Variation ID: 528342). 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 not expected to disrupt ABCD1 protein function. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251421	SCV001427012	uncertain significance	not specified	2021-07-12	criteria provided, single submitter	clinical testing	Variant summary: ABCD1 c.739G>A (p.Ala247Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-06 in 176009 control chromosomes (gnomAD). c.739G>A has been reported in the literature in individuals affected with Adrenoleukodystrophy during ALD newborn screening without providing additional details (Matteson_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000633488	SCV001736723	likely pathogenic	Adrenoleukodystrophy	2021-05-26	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000633488	SCV002045755	uncertain significance	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003139959	SCV003824449	uncertain significance	not provided	2022-02-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000633488	SCV002084610	uncertain significance	Adrenoleukodystrophy	2020-08-31	no assertion criteria provided	clinical testing