ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.676G>A (p.Ala226Thr) (rs763835246)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000412334 SCV000485691 likely pathogenic Classic homocystinuria 2016-01-29 criteria provided, single submitter clinical testing
Invitae RCV000412334 SCV001412523 pathogenic Classic homocystinuria 2019-10-25 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 226 of the CBS protein (p.Ala226Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with homocystinuria (PMID: 14635102, 21520339, 15365998). ClinVar contains an entry for this variant (Variation ID: 370382). This variant has been reported to affect CBS protein function (PMID: 14635102, 22267502, 20066033, 16429402, 17540596, 9590298). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001527049 SCV001737881 likely pathogenic Homocystinuria 2021-06-06 criteria provided, single submitter clinical testing Variant summary: CBS c.676G>A (p.Ala226Thr) results in a non-conservative amino acid change located in the Pryridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251378 control chromosomes. c.676G>A has been reported in the literature in individuals affected with mild Homocystinuria who are responsive to treatment with Pyridoxine (Vitamin-B6) (example, Kruger_2003, Linnebank_2004, Cozar_2011). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal CBS enzyme activity (example, Kruger_2003, Urreizti_2006). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Child Health and Human Development Program,Research Institute of the McGill University Health Center RCV000412334 SCV001424699 pathogenic Classic homocystinuria no assertion criteria provided clinical testing The c.676G>A (A226T) was identified in a patients of French Canadian origin in compound heterozygote with c.313C>G (L105V). Clinical characteristics included lens dislocation and elevated fasting homocysteine. Patient had no intellectual impairment and responds to treatment with vitamin B6.

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