Submissions for variant NM_000071.3(CBS):c.1280C>T (p.Pro427Leu)

gnomAD frequency: 0.00003  dbSNP: rs863223434

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000197292	SCV000249714	pathogenic	not provided	2014-12-09	criteria provided, single submitter	clinical testing	p.Pro427Leu (CCG>CTG): c.1280 C>T in exon 14 of the CBS gene (NM_000071.2). The P427L mutation in the CBS gene has been reported in one individual with a diagnosis of homocystinuria, based on clinical and biochemical findings (Mendes et al., 2014a). This individual was compound heterozygous for the P427L mutation and the S500L mutation. Functional studies showed that P427L causes impaired CBS enzyme activation by its allosteric activator, S-adenosylmethionine (Mendes et al., 2014a; Mednes et al., 2014b). P427L results in a semi-conservative amino acid substitution at a position that is conserved across species. Mutations in nearby residues (P422L, T434N, I435T) have been reported in association with homocystinuria, further supporting the functional importance of this region of the protein. Furthermore, the P427L mutation was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, P427L in the CBS gene is interpreted as a disease-causing mutation. This variant was found in TAADV2-1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000584030	SCV002766586	uncertain significance	not specified	2022-11-07	criteria provided, single submitter	clinical testing	Variant summary: CBS c.1280C>T (p.Pro427Leu) results in a non-conservative amino acid change located in the CBS domain (IPR000644) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 187750 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1280C>T has been reported in the literature in the compound heterozygous state in an individual affected with Homocystinuria (e.g. Mendes_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Homocystinuria. Two publications report experimental evidence evaluating an impact on protein function. They found the variant protein had similar enzymatic activity when compared to the WT protein, but did note that its basal activity was slightly increased and thus upon activation it did not show the same relative increase in activity as the WT protein (e.g. Mendes_2013, Mendes_2014), however it is not yet clear if this could result in pathogenicity. One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV002517170	SCV003471323	uncertain significance	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2022-02-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 427 of the CBS protein (p.Pro427Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with homocystinuria (PMID: 23974653). ClinVar contains an entry for this variant (Variation ID: 212867). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CBS function (PMID: 23974653, 25044645). 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.
Baylor Genetics	RCV003462306	SCV004213879	likely pathogenic	Classic homocystinuria	2024-02-20	criteria provided, single submitter	clinical testing
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000584030	SCV000692243	uncertain significance	not specified	2016-03-15	no assertion criteria provided	clinical testing