The relationship between CBS and classic homocysteinuria, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of March 26th, 2019. CBS encodes cystathione beta-synthase which catalyses the first step of the transsulfuration pathway, from homocysteine to cystathione. Variants in CBS were first reported in humans with this disorder in 1992 (Kozich and Kraus, PMID 1301198). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Twenty-one unique variants were curated (missense, nonsense, frameshift, and splice site) in 15 probands from 8 publications, and three of these probands each had two affected siblings in whom CBS variants were identified (Kozich and Kraus, 1992, PMID 1301198; De Franchis et al, 1999, PMID 10408774; Sebastio et al, 1999, PMID 7762555; Urreizti et al, 2003, PMID 12815602; Katsushima et al, 2006, PMID 16307898; Suri et al, 2014, PMID 25455305; Gong et al, 2015, PMID 26667307; Li et al, 2018, PMID 29508359). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism for disease is biallelic loss of function. This gene-disease relationship is supported by the biochemical function of CBS, which is consistent with the biochemical features in patients with homocystinuria (including elevated plasma total homocysteine and methionine) (Selim et al, 1959, PMID 13654400; Jhee and Kruger, 2005, PMID 15890029), functional studies in yeast, bacteria, and cultured cells, including chaperone studies in fibroblasts from patients with homocystinuria (Shan et al, 1998, PMID 9590298; Melenovská et al, 2018, PMID 25331909), as well as the biochemical and clinical features of mouse models (Gupta et al, 2009, PMID 18987302) and enzyme replacement studies in mice (Matjan et al, 2018, PMID 29398487). More information is available but the maximum experimental evidence score (6 points) has been reached. In summary, CBS is definitively associated with classic homocystinuria. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Aminoacidopathy Gene Curation Expert Panel on April 12, 2019.
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