ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.770C>T (p.Thr257Met) (rs758236584)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169294 SCV000220612 likely pathogenic Homocystinuria due to CBS deficiency 2014-08-21 criteria provided, single submitter literature only
GeneDx RCV000197988 SCV000249729 pathogenic not provided 2014-09-09 criteria provided, single submitter clinical testing p.Thr257Met (ACG>ATG): c.770 C>T in exon 9 of the CBS gene (NM_000071.2). The T257M mutation in the CBS was initially reported as homozygous in one Italian individual diagnosed with homocystinuria who was nonresponsive to cofactor treatment (Sebastio et al., 1995). This individual's parents were first-cousins and were both heterozygous for T257M, as were the proband's two siblings (Sebastio et al., 1995). In vitro functional studies show that T257M leads to a marked decrease in CBS enzymatic activity (Sebastio et al., 1995; Lee et al., 2005; Yadav et al., 2012). T257M has also been reported in one Korean individual with homocystinuria (Lee et al., 2005). T257M results in a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. Mutations in nearby residues (L251P, G259D, G259S) have been reported in association with homocystinuria, further supporting the functional importance of this region of the protein. Furthermore, the T257M mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, T257M in the CBS gene is interpreted as a disease-causing mutation. This variant was found in TAAD
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000169294 SCV000930258 uncertain significance Homocystinuria due to CBS deficiency 2019-04-27 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000790997 SCV000930259 uncertain significance Hyperhomocysteinemia 2019-04-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780084 SCV000917110 pathogenic Homocystinuria 2018-12-24 criteria provided, single submitter clinical testing Variant summary: CBS c.770C>T (p.Thr257Met) 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 4.7e-05 in 274572 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CBS causing Homocystinuria (4.7e-05 vs 0.003), allowing no conclusion about variant significance. c.770C>T has been reported in the literature in multiple homozygous (Sebastio 1995, Zaidi 2012) and compound heterozygous (e.g. Lee 2005) individuals affected with Homocystinuria. Moreover, the variant was shown to segregate with the disease in one of these families (Sebastio 1995). These data indicate that the variant is very likely to be associated with disease. These publications also reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Sebastio 1995, Lee 2005). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169294 SCV000649849 pathogenic Homocystinuria due to CBS deficiency 2017-05-07 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 257 of the CBS protein (p.Thr257Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs758236584, ExAC 0.02%). This variant has been reported in the literature in several unrelated individuals in the compound heterozygous state affected with homocystinuria (PMID: 16205833, 16479318) with evidence of co-segregation with disease in two families with the variant in the homozygous state in the affected individuals (PMID: 21517828, 7762555). ClinVar contains an entry for this variant (Variation ID: 188927). Experimental studies have shown that this missense change leads to a sharp decrease of CBS enzymatic activity (PMID: 7762555, 22267502, 16205833, 22977242). For these reasons, this variant has been classified as Pathogenic.

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