ClinVar

Description

Variant summary: The CBS c.1224-2A>C variant (alternatively also known as IVS11-2A>C) involves the alteration of a highly conserved intronic nucleotide in the canonical splice acceptor site in intron 13, and is expected to cause aberrant gene splicing. 5/5 splice prediction tools also predict abrogation of the splice acceptor site. Consistent to these predictions, this variant is shown to cause exon skipping resulting in an in-frame deletion of exon 12 (amino acids W408 to G453) (Kozick_1992); exon 12 is involved in encoding the CBS domain of the protein (InterPro). In addition, expression of this variant in bacterial (E. coli) system shows that this variant not only leads to abrogation of catalytic activity, but also non-responsiveness to chaperones used to treat the CBS deficiency (Orendac _2004, Kopecka_2011). This variant was found in 7/45474 control chromosomes from ExAC at a frequency of 0.0001539, which does not exceed the estimated maximal expected allele frequency of a pathogenic CBS variant (0.0030414). This variant has been reported in several patients with CBS deficiency in homozygous as well as compound heterozygous with other pathogenic or potentially pathogenic variants including evidence of cosegregation with disease. It is predominantly found in patients from Central Europe, where it has been found on in average 14% of mutant alleles with evidence of founder effect (Linnebank_2004). Available patient and functional data indicate that this variant is likely a severe mutation. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.