ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.1006C>T (p.Arg336Cys) (rs398123151)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169310 SCV000220632 pathogenic Classic homocystinuria 2014-08-25 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078105 SCV000225195 pathogenic not provided 2012-07-26 criteria provided, single submitter clinical testing
GeneDx RCV000078105 SCV000249700 pathogenic not provided 2018-10-05 criteria provided, single submitter clinical testing The R336C pathogenic variant in the CBS gene has previously been reported in the homozygous and compoundheterozygous state in individuals with homocystinuria (de Franchis et al., 1999; Urreizti et al., 2003; El-Said et al.,2006; Kwok et al., 2011; Zaidi et al., 2012; Lims et al., 2013; Alcaide et al., 2015; El Bashir et al., 2015). Inaddition, R336C considered a founder mutation accounting for almost all CBS deficiency in Qatar, affectingapproximately 1 in 1,800 births (El Bashir et al., 2015). In addition, a differentlikely pathogenic missense variant affecting the same residue (R336H) has previously been reported in association inhomocystinuria (Coude et al., 1998; Mayfield et al., 2012).The R336C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000Genomes Consortium et al., 2015; Exome Variant Server). The R336C variant is a non-conservative amino acidsubstitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, sizeand/or other properties. This substitution occurs at a position that is conserved across species. Functional studieshave demonstrated that in the homozygous or compound heterozygous state, R336C leads to absence of the CBSenzyme activity (de Franchis et al., 1999; Urreizti et al., 2003; Urreizti et al., 2006).
Fulgent Genetics,Fulgent Genetics RCV000169310 SCV000893553 pathogenic Classic homocystinuria 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000169310 SCV000945559 pathogenic Classic homocystinuria 2019-02-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 336 of the CBS protein (p.Arg336Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs398123151, ExAC 0.003%). This variant has been observed to be homozygous or in combination with another CBS variant in individuals affected with homocystinuria (PMID: 12815602, 16205833, 21517828), and has been shown to segregate with disease in a family (PMID: 21517828). ClinVar contains an entry for this variant (Variation ID: 92423). This variant has been reported to affect CBS protein function (PMID: 10408774, 16429402, 16205833, 26464485). This variant disrupts the p.Arg336 amino acid residue in CBS. Other variant(s) that disrupt this residue have been observed in individuals with CBS-related disease (PMID: 9870207, 23974653, 25218699), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000169310 SCV001133148 likely pathogenic Classic homocystinuria 2019-09-26 no assertion criteria provided clinical testing

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