Submissions for variant NM_000071.3(CBS):c.1265C>T (p.Pro422Leu)

dbSNP: rs28934892

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522394	SCV000617613	uncertain significance	not provided	2020-10-29	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22985361, 22267502, 20490928, 20308073, 19888216, 20506325, 22612060, 12007221, 10780316, 25331909)
Counsyl	RCV000675050	SCV000800491	uncertain significance	Classic homocystinuria	2017-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000675050	SCV000914971	uncertain significance	Classic homocystinuria	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.
Ambry Genetics	RCV002444412	SCV002681405	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-03-05	criteria provided, single submitter	clinical testing	The p.P422L variant (also known as c.1265C>T), located in coding exon 12 of the CBS gene, results from a C to T substitution at nucleotide position 1265. The proline at codon 422 is replaced by leucine, an amino acid with similar properties. This variant has been reported in at least two individuals with high homocysteine levels, one of whom had history of thrombosis and the other ischemic attacks, but both lacked significant connective tissue findings; these individuals were both compound heterozygotes with a second CBS variant, although phase information was not provided (Gaustadnes M et al. Thromb. Haemost., 2000 Apr;83:554-8; Maclean KN et al. Hum. Mutat., 2002 Jun;19:641-55). Results of functional studies have shown no significant impact on protein expression and stability, but possible differences in protein interactions were suggested in some assays; the clinical impact of these findings is unclear (Maclean KN et al. Hum. Mutat., 2002 Jun;19:641-55; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23; Hnízda A et al. Biochemistry, 2012 06;51:4755-63; Melenovská P et al. J. Inherit. Metab. Dis., 2015 Mar;38:287-94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000152	SCV003271519	uncertain significance	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2021-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 422 of the CBS protein (p.Pro422Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with homocystinuria (PMID: 12007221). ClinVar contains an entry for this variant (Variation ID: 129). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CBS function (PMID: 12007221, 20506325, 22267502, 22612060, 25331909). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM	RCV000000152	SCV000020295	pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2000-04-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000675050	SCV001461063	uncertain significance	Classic homocystinuria	2020-09-16	no assertion criteria provided	clinical testing