ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.430G>C (p.Glu144Gln) (rs121964966)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000538588 SCV000649838 uncertain significance Classic homocystinuria 2018-01-17 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 144 of the CBS protein (p.Glu144Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs121964966, ExAC 0.02%). This variant has not been reported in the literature in individuals with CBS-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Glu144Lys) has been determined to be pathogenic (PMID: 12124992, 7611293, 10215408, 22267502, 20506325, 25331909). This suggests that the glutamic acid residue is critical for CBS protein function and that other missense substitutions at this position may also be pathogenic. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Child Health and Human Development Program,Research Institute of the McGill University Health Center RCV000538588 SCV001424720 pathogenic Classic homocystinuria no assertion criteria provided clinical testing The c.430G>C (E144Q) was identified in a patient of Eastern European origin in compound heterozygote with IVS11-2 A>C. Clinical characteristics included lens dislocation and elevated fasting homocysteine. Patient had no intellectual impairment and does not respond to treatment with vitamin B6.

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