ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.302T>C (p.Leu101Pro) (rs786204757)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169617 SCV000221143 likely pathogenic Classic homocystinuria 2015-02-18 criteria provided, single submitter literature only
Invitae RCV000169617 SCV000826966 pathogenic Classic homocystinuria 2020-08-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 101 of the CBS protein (p.Leu101Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the homozygous or compound-heterozygous state in several individuals and families affected with cystathionine β-synthase (CBS) deficiency (PMID: 9889017, 12124992, 14635102). ClinVar contains an entry for this variant (Variation ID: 189185). Experimental studies in yeast and E. coli have shown that this missense change results in complete loss of enzymatic activity (PMID: 22267502, 20066033, 14635102, 12124992). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001251397 SCV001426983 pathogenic Homocystinuria 2020-07-20 criteria provided, single submitter clinical testing Variant summary: CBS c.302T>C (p.Leu101Pro) 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 was absent in 251342 control chromosomes (gnomAD). c.302T>C has been reported in the literature, in the homozygous or compound heterozygous state, in multiple individuals affected with Homocystinuria (e.g. Gallagher_1998, Gaustadnes_2002). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to be devoid of CBS activity (e.g. Gaustadnes_2002, Singh_2010, Mayfield_2012). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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