ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.526G>A (p.Glu176Lys) (rs762065361)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000781199 SCV000919084 pathogenic Homocystinuria 2017-12-07 criteria provided, single submitter clinical testing Variant summary: The CBS c.526G>A (p.Glu176Lys) variant located in the pyridoxal-phosphate dependent enzyme domain (via InterPro) involves the alteration of a conserved nucleotide and 4/5 in silico tools predict a damaging outcome for this variant. Multiple functional studies, Janocik_2001, Lu_2012, and Hnizda_2012, support these predictions with observations that the variant impedes proper CBS protein function. This variant is absent in 184408 control chromosomes (gnomAD). Multiple publications have cited the variant in a homozygous and compound heterozygote patients. However, to our knowledge, the variant of interest has not been citied by reputable clinical diagnostic laboratories. Taken together, this variant is classified as pathogenic.
Invitae RCV001220158 SCV001392134 pathogenic Classic homocystinuria 2019-06-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 176 of the CBS protein (p.Glu176Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with homocystinuria (PMID: 9266356, 22353391, 30732165). ClinVar contains an entry for this variant (Variation ID: 633144). This variant has been reported to affect CBS protein function (PMID: 20506325, 22267502, 22353391). For these reasons, this variant has been classified as Pathogenic.
Child Health and Human Development Program,Research Institute of the McGill University Health Center RCV001220158 SCV001424585 pathogenic Classic homocystinuria no assertion criteria provided clinical testing The c.526G>A (E176K) was identified in a patients of Eastern European origin in compound heterozygote with c.1039G>A (G347S). Clinical characteristics included lens dislocation and elevated fasting homocysteine. Patients had no intellectual impairment and do not respond to treatment with vitamin B6.

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