Submissions for variant NM_005050.4(ABCD4):c.1588C>T (p.Gln530Ter)

dbSNP: rs767795583

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000707417	SCV000836515	pathogenic	Methylmalonic acidemia with homocystinuria, type cblJ	2017-10-18	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ABCD4 are known to be pathogenic (PMID: 22922874). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with ABCD4-related disease. This variant is present in population databases (rs767795583, ExAC 0.002%). This sequence change creates a premature translational stop signal (p.Gln530*) in the ABCD4 gene. It is expected to result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265867	SCV002548358	likely pathogenic	Cobalamin C disease	2022-05-11	criteria provided, single submitter	clinical testing	Variant summary: ABCD4 c.1588C>T (p.Gln530X) 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 observed in association with inborn error of vitamin B12 metabolism in the HGMD database. The variant allele was found at a frequency of 4e-06 in 249354 control chromosomes. To our knowledge, no occurrence of c.1588C>T in individuals affected with Methylmalonic Acidemia With Homocystinuria and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000707417	SCV004047863	likely pathogenic	Methylmalonic acidemia with homocystinuria, type cblJ		criteria provided, single submitter	clinical testing	The stop gained c.1588C>T (p.Gln530Ter) variant has been submitted to ClinVar as Pathogenic but no evidences are provided for independent assessment. This p.Gln530Ter variant has allele frequency of 0.00040% in the gnomAD and novel (not in any individuals) in 1000 genome database. The nucleotide change c.1588C>T in ABCD4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another variant in ABCD4 gene, the molecular diagnosis can not be confirmed. The above variant has also been detected in the proband's father.