Submissions for variant NM_005050.4(ABCD4):c.423C>G (p.Asn141Lys)

gnomAD frequency: 0.00001  dbSNP: rs776529140

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844616	SCV002103766	pathogenic	Cobalamin C disease	2022-02-09	criteria provided, single submitter	clinical testing	Variant summary: ABCD4 c.423C>G (p.Asn141Lys) 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 2.4e-05 in 250048 control chromosomes. c.423C>G has been reported in the literature as a homozygous genotype in multiple comprehensively analyzed individuals affected with Methylmalonic Acidemia With Homocystinuria (example, Kim_2012, Takeichi_2015, Liu_2019). These data indicate that the variant is very likely to be associated with disease. At least two publications reports experimental evidence evaluating an impact on protein function in-vitro (example, Fettelschoss_2017, Kitai_2021). The most pronounced variant effect results in complete abolishment of cobalamin transport with preserved ATP'ase activity (Kitai_2021) and decreased interaction (approximately 30% of WT) of the mutant ABCD4 protein with the membrane protein LMBD1 required for lysosomal release of cobalamin (Fettelschoss_2017). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005095315	SCV005837276	likely pathogenic	Methylmalonic acidemia with homocystinuria, type cblJ	2024-08-13	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 141 of the ABCD4 protein (p.Asn141Lys). This variant is present in population databases (rs776529140, gnomAD 0.04%). This missense change has been observed in individuals with clinical features of ABCD4-related conditions (PMID: 23141461, 25234635, 30651581). ClinVar contains an entry for this variant (Variation ID: 1343599). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ABCD4 function (PMID: 28572511, 33845046). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.