Submissions for variant NM_000071.2(CBS):c.1265C>T (p.Pro422Leu) (rs28934892)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522394	SCV000617613	uncertain significance	not provided	2017-09-06	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CBS gene. The P422L variant has been reported in one patient with homocystinuria who harbored an additional variant in the CBS gene (Maclean et al., 2002). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P422L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, while some functional studies studies suggest the presence of the P422L variant may alter protein interactions under various experimental conditions, it is not known whether these findings are biological or clinically relevant in vivo (Maclean et al., 2002; Mayfield et al., 2012).
Counsyl	RCV000675050	SCV000800491	uncertain significance	Homocystinuria due to CBS deficiency	2017-01-31	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000675050	SCV000914971	uncertain significance	Homocystinuria due to CBS deficiency	2018-11-26	criteria provided, single submitter	clinical testing	The CBS c.1265C>T (p.Pro422Leu) variant is a missense variant that has been reported in a compound heterozygous state in at least one individual with a mild form of homocystinuria characterized by high Hcy levels and episodic transient ischemic attacks but no external features or connective tissue disorders characteristic of the disease (Gaustadnes et al. 2010; Maclean et al. 2002). This variant was absent from 100 control alleles and is not reported in the 1000 Genomes Project, Exome Sequencing Project, Exome Aggregation Consortium, or Genome Aggregation Database despite its location of good sequencing coverage. It is therefore presumed to be rare. Functional studies of the variant, which is located in the regulatory domain, conducted in E. coli, CHO-K1 cells, and yeast suggest the p.Pro422Leu variant protein is expressed at the same level as the wild type protein, is thermodynamically stable, and does not show reduced catalytic activity; however, experiments investigating the variant's effect on regulation by S-adenosylmethionine, which is required for in vivo regulation of homocysteine levels, produced conflicting results (Maclean et al. 2002; Kozich et a. 2010; Majtan et al. 2010; Mayfield et al. 2012; Hnízda et al. 2012; Melenovská et al. 2015). The evidence for this variant is limited. The p.Pro422Leu variant is thus classified as of uncertain significance but suspicious for pathogenicity for homocystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
OMIM	RCV000000152	SCV000020295	pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2000-04-01	no assertion criteria provided	literature only