ClinVar Genomic variation as it relates to human health

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #188927; Landrum et al., 2016); In vitro functional studies show a marked decrease in CBS enzymatic activity (Sebastio et al., 1995; Lee et al., 2005; Yadav et al., 2012); 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: 22977242, 21517828, 22267502, 7762555, 29600437, 29508359, 16205833, 23685761, 7967489, 16479318, 31589614)

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 257 of the CBS protein (p.Thr257Met). This variant is present in population databases (rs758236584, gnomAD 0.01%). This missense change has been observed in individual(s) with homocystinuria (PMID: 7762555, 16205833, 16479318, 21517828). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188927). 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: 7762555, 16205833, 22267502, 22977242). For these reasons, this variant has been classified as Pathogenic.

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.

ACMG categories: PS3,PM1,PM2,PP3,PP5

The p.Thr257Met variant in CBS has been reported in at least 7 individuals with homocystinuria (4 homozygous and 3 compound heterozygous) and segregated with disease in 2 affected individuals from 2 families (Ibrahim 2018, Lee 2005, Li 2018, Sebastio 1995, Urreizti 2006, Zaidi 2012). It has also been identified in 12/279982 total chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID 188927). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Mayfield 2012, Yadav 2012, Sebastio 1995, Lee 2005). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive homocystinuria. ACMG/AMP Criteria applied: PS3, PM3_Strong, PM2_Supporting, PP1, PP3, PP4.