ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.959T>C (p.Val320Ala) (rs781567152)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000410016 SCV000486482 likely pathogenic Classic homocystinuria 2016-06-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780081 SCV000917107 likely pathogenic Homocystinuria 2018-10-15 criteria provided, single submitter clinical testing Variant summary: CBS c.959T>C (p.Val320Ala) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 245462 control chromosomes (gnomAD and publication). c.959T>C has been reported in the literature in individuals affected with Homocystinuria (Guttormsen_2001, Kruger_2003). These data indicate that the variant is likely to be associated with disease. Multiple publications have assessed the variant for functional implications, which shown that colony growth was slow to grow in yeast cells and a homozygous patient had 36% enzyme activity (Kim_1997, Kruger_2003, Mayfield_2012). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the parent as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000797 SCV001157857 pathogenic not specified 2018-10-01 criteria provided, single submitter clinical testing The CBS c.959T>C; p.Val320Ala variant (rs781567152) is reported in the literature in multiple individuals affected with homocystinuria in both the homozygous state and in individuals with a second pathogenic variant (Kim 1997, Kruger 2003). This variant is reported in ClinVar (Variation ID: 371028), and it is found on only four chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. Another variant at this codon (p.Val320Gly) has been reported in an individual with homocystinuria and is considered pathogenic (Lu 2012). The valine at codon 320 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that the p.Val320Ala variant is deleterious. Consistent with these predictions, functional analyses demonstrate that the p.Val320Ala variant exhibits significantly lower enzymatic activity than wildtype protein (Kruger 2003, Singh 2010) and fails to rescue yeast growth on media lacking a source of cysteine (Kim 1997, Mayfield 2012). Based on available information, this variant is considered to be pathogenic. References: Kim CE et al. Functional modeling of vitamin responsiveness in yeast: a common pyridoxine-responsive cystathionine beta-synthase mutation in homocystinuria. Hum Mol Genet. 1997 Dec;6(13):2213-21. Kruger WD et al. Cystathionine beta-synthase deficiency in Georgia (USA): correlation of clinical and biochemical phenotype with genotype. Hum Mutat. 2003 Dec;22(6):434-41. Lu YH et al. Homocystinuria in Taiwan: an inordinately high prevalence in an Austronesian aboriginal tribe, Tao. Mol Genet Metab. 2012 Apr;105(4):590-5. Mayfield JA et al. Surrogate genetics and metabolic profiling for characterization of human disease alleles. Genetics. 2012 Apr;190(4):1309-23. Singh LR et al. Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70. PLoS Genet. 2010 Jan;6(1):e1000807.

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