Submissions for variant NM_000033.4(ABCD1):c.1679C>T (p.Pro560Leu)

dbSNP: rs398123105

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723625	SCV000109787	pathogenic	not provided	2013-04-30	criteria provided, single submitter	clinical testing
Invitae	RCV000077958	SCV000629992	pathogenic	Adrenoleukodystrophy	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 560 of the ABCD1 protein (p.Pro560Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with X-linked adrenoleukodystrophy (PMID: 7717396, 8651290, 20661612, 21700483, 23566833, 24719134). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 92320). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000723625	SCV001783337	pathogenic	not provided	2022-05-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34997422, 34649108, 10190819, 21889498, 21068741, 20661612, 8651290, 24719134, 11748843, 20800589, 21300044, 22479560, 23864971, 22189598, 12530690, 23566833, 21700483, 7717396)
Revvity Omics, Revvity	RCV000723625	SCV002022833	pathogenic	not provided	2022-08-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000077958	SCV002045837	pathogenic	Adrenoleukodystrophy	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000077958	SCV002547816	pathogenic	Adrenoleukodystrophy	2022-05-13	criteria provided, single submitter	clinical testing	Variant summary: ABCD1 c.1679C>T (p.Pro560Leu) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183088 control chromosomes. c.1679C>T has been reported in the literature in many individuals affected with Adrenoleukodystrophy (example Braun_1995, Feigenbaum_1996, Takano_1999, Kemp_2001, Jack_2013, Capalbo_2021). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002399466	SCV002710978	pathogenic	Inborn genetic diseases	2017-10-10	criteria provided, single submitter	clinical testing	The p.P560L pathogenic mutation (also known as c.1679C>T), located in coding exon 7 of the ABCD1 gene, results from a C to T substitution at nucleotide position 1679. The proline at codon 560 is replaced by leucine, an amino acid with similar properties. This mutation has been reported in multiple affected males with the childhood cerebral form of X-linked adrenoleukodystrophy and adrenomyeloneuropathy (AMN) (Braun A et al. Am. J. Hum. Genet., 1995 Apr;56:854-61; Feigenbaum V et al. Am. J. Hum. Genet., 1996 Jun;58:1135-44; Shukla P et al. Clin. Chim. Acta, 2011 Nov;412:2289-95; Wang Y et al. Mol. Genet. Metab. Jun;104:160-6; Park HJ et al. Yonsei Med. J., 2014 May;55:676-82; Jack GH et al. Case Rep Neurol Med, 2013 Jun;2013:491790). In addition, adrenoleukodystrophy protein (ALDP) analysis in cells from affected individuals demonstrated a reduced level or absent protein compared to wild type (Feigenbaum V et al. Am. J. Hum. Genet., 1996 Jun;58:1135-44). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Baylor Genetics	RCV000077958	SCV003835955	pathogenic	Adrenoleukodystrophy	2022-12-04	criteria provided, single submitter	clinical testing
Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	RCV000077958	SCV004024557	pathogenic	Adrenoleukodystrophy	2023-08-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003483467	SCV004231795	benign	not specified	2023-05-12	criteria provided, single submitter	research