Submissions for variant NM_000033.4(ABCD1):c.1415_1416del (p.Gln472fs) (rs387906494)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000516943	SCV000109780	pathogenic	not provided	2015-06-10	criteria provided, single submitter	clinical testing
Counsyl	RCV000012055	SCV000486281	pathogenic	Adrenoleukodystrophy	2016-07-12	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000516943	SCV000612228	pathogenic	not provided	2018-12-11	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
GeneDx	RCV000516943	SCV000617388	pathogenic	not provided	2017-05-30	criteria provided, single submitter	clinical testing	The c.1415_1416delAG pathogenic variant in the ABCD1 gene has been previously reported in multiple unrelated individuals as a common variant associated with varying forms of X-linked adrenoleukodystrophy (Kemp et al., 2004; Feigenbaum et al., 1996; Kemp et al., 2001). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1415_1416delAG variant causes a frameshift starting with codon Glutamine 472, changes this amino acid to a Arginine residue, and creates a premature Stop codon at position 83 of the new reading frame, denoted p.Gln472ArgfsX83. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, we interpret c.1415_1416delAG as a pathogenic variant.
Invitae	RCV000012055	SCV000629988	pathogenic	Adrenoleukodystrophy	2019-08-12	criteria provided, single submitter	clinical testing	This sequence change deletes 2 nucleotides from exon 5 of the ABCD1 mRNA (c.1415_1416delAG), causing a frameshift at codon 472. This creates a premature translational stop signal (p.Gln472Argfs*83) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCD1 are known to be pathogenic. This particular variant has been reported in the literature in several individuals affected with childhood or adult-onset adrenoleukodystrophy or adrenomyeloneuropathy (PMID: 8048932, 23154058, 23768953, 23566833, 22479560, 7849723). This variant is also referred to as 1801delAG in the literature. ClinVar contains an entry for this variant (Variation ID: 11303). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV000516943	SCV000883323	pathogenic	not provided	2017-11-09	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000012055	SCV001338292	pathogenic	Adrenoleukodystrophy	2020-02-10	criteria provided, single submitter	clinical testing	Variant summary: ABCD1 c.1415_1416delAG (p.Gln472ArgfsX83) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 182139 control chromosomes. c.1415_1416delAG has been extensively reported in the literature in multiple individuals from diverse ethnic cohorts affected with Adrenoleukodystrophy. Some of the original reports of its identification are ascertained here (example, Feigenbaum_1996, Kemp_1994, Kok_1995, Ligtenberg_1995, Coll_2005, Pan_2005). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a complete absence of protein expression (example, Feigenbaum_1996, Coll_2005). Seven 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000012055	SCV001429086	pathogenic	Adrenoleukodystrophy	2018-06-19	criteria provided, single submitter	clinical testing	This variant was identified as hemizygous
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000012055	SCV001429638	pathogenic	Adrenoleukodystrophy	2020-07-20	criteria provided, single submitter	clinical testing	A hemizygous 2 base pair deletion in exon 5 of the ABCD1 gene that results in a frameshift and premature truncation of the protein 83 amino acids downstream to codon 472 was detected. The observed variant c.1415_1416delAG (p.Gln472ArgfsTer83) has been reported previously in patients affected with adrenoleukodystrophy (Niu et al. 2013) and also classified as pathogenic in the ClinVar database. The variant has not been reported in the 1000 genomes and gnomAD databases. The reference region is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000516943	SCV001448165	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
OMIM	RCV000012055	SCV000032289	pathogenic	Adrenoleukodystrophy	1994-10-01	no assertion criteria provided	literature only
GeneReviews	RCV000012055	SCV001156246	pathogenic	Adrenoleukodystrophy	2018-02-15	no assertion criteria provided	literature only