Submissions for variant NM_000071.3(CBS):c.494G>A (p.Cys165Tyr)

gnomAD frequency: 0.00001  dbSNP: rs1347651454

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587735	SCV000695306	pathogenic	Homocystinuria	2017-08-24	criteria provided, single submitter	clinical testing	Variant summary: The CBS c.494G>A (p.Cys165Tyr) variant causes a missense change involving the alteration of a conserved nucleotide located in the Tryptophan synthase beta subunit-like PLP-dependent enzyme domain.. 5/5 in silico tools predict a damaging outcome for this variant. An enzymatic assay using yeast showed non-functional CBS enzyme associated with this variant (Mayfield_2012), and in at least one patient homozygous for the variant, activity in fibroblasts was non-detectable (Kluijtmans_1999). This variant was not found in the large control database ExAC in 29004 control chromosomes and was reported in multiple patients with homocystinuria (Kluijtmans_1999, Magner_2011). Taken together, this variant is classified as pathogenic.
Ambry Genetics	RCV002315881	SCV000738494	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2016-10-26	criteria provided, single submitter	clinical testing	The p.C165Y pathogenic mutation (also known as c.494G>A), located in coding exon 4 of the CBS gene, results from a G to A substitution at nucleotide position 494. The cysteine at codon 165 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been previously reported as detected in the homozygous state and compound heterozygous state with other mutations in individuals with CBS deficiency or homocystinuria (Kluijtmans LA et al. Hum Genet. 1995;96:249-50; Kluijtmans LA et al. Am J Hum Genet. 1999;65(1):59-67; Janosík M et al. Am J Hum Genet. 2001;68:1506-13; Gaustadnes M et al. Hum Mutat. 2002;20:117-26; Magner M et al. J Inherit Metab Dis. 2011;34:33-7; Mayfield JA et al. Genetics. 2012;190:1309-23). In addition, fibroblasts derived from patients homozygous for this alteration have deficient CBS activity, and this variant results in reduced enzyme activity in multiple other in vitro studies (Gordon RB et al. Hum Mutat. 1998;11:332; Kluijtmans LA et al. Am J Hum Genet. 1999;65(1):59-67; Janosík M et al. Am J Hum Genet. 2001;68:1506-13; Mayfield JA et al. Genetics. 2012;190:1309-23; Melenovská P et al. J Inherit Metab Dis. 2015;38:287-94). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002232223	SCV000941440	pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 165 of the CBS protein (p.Cys165Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with homocystinuria (PMID: 7635485, 10215408, 10364517, 12124992, 18708589, 20567906). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 495531). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 10215408, 11359213, 20490928, 20506325, 22267502). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University Hospital Muenster	RCV002287426	SCV002577800	pathogenic	See cases	2021-12-16	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PM1,PM2,PP1,PP3,PP5
Baylor Genetics	RCV003459454	SCV004213874	pathogenic	Classic homocystinuria	2023-09-07	criteria provided, single submitter	clinical testing