Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000196859 | SCV000249677 | pathogenic | not provided | 2021-10-25 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); The p.(R121C) variant was determined to be nonfunctional in yeast complementation studies (Mayfield et al., 2021); 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: 20455263, 10338090, 21520339, 16307898, 12686134, 22267502) |
| Illumina Laboratory Services, |
RCV000475484 | SCV000436228 | likely pathogenic | Classic homocystinuria | 2018-04-23 | criteria provided, single submitter | clinical testing | The CBS c.361C>T (p.Arg121Cys) missense variant has been reported in three studies in which it is identified in a homozygous state in one individual and in a compound heterozygous state in a second individual in trans with a known pathogenic variant, both diagnosed with CBS deficiency (Katushima et al. 2006; Cozar et al. 2011). The variant has also been reported in a compound heterozygous state in one individual described as asymptomatic and in an additional two patient alleles of unknown zygosity (Kraus et al. 1999). In one study, the p.Arg121Cys variant was absent from 100 ethnically matched control chromosomes but is reported at a frequency of 0.000060 in the European (non-Finnish) population of the Exome Aggregation Consortium. Contradictory results were obtained in functional studies in yeast: Wei et al. (2010) describe the variant as neutral whereas Mayfield et al. (2012) describe the variant as non-functional. Six prediction algorithms predict the variant to be deleterious (Wei et al. 2010). The Arg121 residue is conserved and involved in important salt-bridge interactions with other residues (Wei et al. 2010). Based on the evidence, the p.Arg121Cys 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. |
| Labcorp Genetics |
RCV002229025 | SCV000543501 | pathogenic | HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED | 2024-06-17 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 121 of the CBS protein (p.Arg121Cys). This variant is present in population databases (rs775992753, gnomAD 0.004%). This missense change has been observed in individuals with homocystinuria (PMID: 10338090, 16307898, 21520339; Invitae). ClinVar contains an entry for this variant (Variation ID: 212842). 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: 22267502). This variant disrupts the p.Arg121 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10338090, 22267502, 22353391). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001192722 | SCV001361017 | likely pathogenic | Homocystinuria | 2022-04-14 | criteria provided, single submitter | clinical testing | Variant summary: CBS c.361C>T (p.Arg121Cys) 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 1.6e-05 in 251102 control chromosomes (gnomAD). The variant, c.361C>T, has been reported in the literature in individuals affected with Homocystinuria, including one homozygote (Kraus_1999, Katsushima_2006, Cozar_2011). These data indicate that the variant is likely to be associated with disease. One publication, (Mayfield_2012), tested the function of this variant in a yeast assay and reported the variant to be non-functional, while a different functional study, also using a yeast assay, reported the variant as neutral (Wei_2010). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV000475484 | SCV004213853 | pathogenic | Classic homocystinuria | 2023-11-27 | criteria provided, single submitter | clinical testing |