ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.361C>T (p.Arg121Cys) (rs775992753)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000196859 SCV000249677 pathogenic not provided 2013-10-08 criteria provided, single submitter clinical testing p.Arg121Cys (CGC>TGC): c.361 C>T in exon 5** of the CBS gene (NM_000071.2). The Arg121Cys mutation in the CBS gene has been reported previously in association with homocystinuria due to CBS deficiency (Krauss J et al., 1999; Katsushima F et al., 2006; Cozar M et al., 2011). This variant was found in TAAD
Illumina Clinical Services Laboratory,Illumina RCV000475484 SCV000436228 likely pathogenic Homocystinuria due to CBS deficiency 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.
Invitae RCV000475484 SCV000543501 pathogenic Homocystinuria due to CBS deficiency 2016-12-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 121 of the CBS protein (p.Arg121Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs775992753, ExAC 0.006%). This variant has been reported as homozygous or compound heterozygous in individuals affected with homocystinuria (PMID: 16307898, 21520339, 10338090, Invitae). ClinVar contains an entry for this variant (Variation ID: 212842). Experimental studies have shown that this variant abolishes enzyme activity in vitro (PMID: 22267502). A different amino acid substitution at this position, p.Arg121Leu, has been considered as likely pathogenic because it has been observed in affected individuals and shown to impair enzyme function (PMID: 22353391, 10338090, 22267502, 22353391). These observations support the clinical significance of this amino acid position. For these reasons, this variant has been classified as Pathogenic.

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