ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.373C>T (p.Arg125Trp) (rs886057100)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000667483 SCV000436227 likely pathogenic Classic homocystinuria 2017-04-27 criteria provided, single submitter clinical testing The CBS c.373C>T (p.Arg125Trp) variant has been reported in three studies in which it is found in a total of five individuals with homocystinuria, including two sets of siblings, all in a compound heterozygous state (Kluijtmans et al. 1999; Urreizti et al. 2003; Chwatko et al. 2007). Control data are unavailable for this variant, and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Functional studies in individual fibroblasts showed that the variant resulted in less than 2.5% of the CBS activity seen in unaffected individuals (Chwatko et al. 2007). Based on the evidence, the p.Arg125Trp variant is classified as likely pathogenic for homocystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV001175468 SCV001339043 pathogenic Homocystinuria 2020-03-30 criteria provided, single submitter clinical testing Variant summary: CBS c.373C>T (p.Arg125Trp) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926) 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 8e-06 in 251030 control chromosomes (gnomAD). c.373C>T has been reported in the literature in multiple compound heterozygous individuals affected with Homocystinuria (Kluijtmans_1999, Urreizti_2003, Karaca_2014). These data indicate that the variant is likely to be associated with disease. Several publications also reported experimental evidence evaluating an impact on protein function, and demonstrated absent or less than 4% residual activities in patient derived fibroblasts (Kluijtmans_1999, Urreizti_2003) and in a bacterial expression system (Urreizti_2006). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000667483 SCV000791939 likely pathogenic Classic homocystinuria 2017-05-31 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.